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Purpose: The influence of cancer development on long-term outcome after lower extremity bypass surgery in patients with critical limb threatening ischemia was investigated. Methods: Patient survival and cancer incidence were recorded for 21,082 patients with peripheral artery disease (PAD) stage III (n = 5631; 26.7%) and stage IV (n = 15,451; 73.3%) registered with the AOK health insurance company in Germany who underwent infrainguinal bypass surgery. All patients were preoperative and in their history cancer-free. Results: After a median follow-up of 44 months, 25.6% of all patients developed cancer (Kaplan–Meier estimated), with no significant differences between patients with PAD stage III and IV (cancer incidence stage III 25.7%, stage IV 25.5%; p = 0.421). In the Cox regression analysis, male gender (HR 1.885; 95% CI 1.714–2.073, p < 0.001) and age over 70 years (HR 1.399; 95% CI 1.285–1.522, p < 0.001) were significant risk factors for the development of cancer. Survival was significantly lower in stage IV (23.4%) compared to stage III (44.5%) (HR 1.720; 95% CI 1.645–1.799, p < 0.001). Cancer was a significant risk factor for overall survival in PAD stage III patients (HR: 1.326; 95% CI 1.195–1.471, p < 0.001) but not in PAD stage IV (HR 0.976; 95% CI 0.919–1.037, p = 0.434). Conclusion: Patients with PAD stage III have significantly better survival after infrainguinal bypass surgery compared to patients with stage IV. While cancer incidence was essential for survival in stage III, it was of no importance in stage IV. [ABSTRACT FROM AUTHOR]