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Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? Methods: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. Results: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. Conclusion: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. Level of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]