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Simple Summary: No standard treatment is defined for relapsed or refractory (r/r) primary CNS lymphoma (PCNSL). However, high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT), an efficient first line treatment in younger PCNSL patients, is commonly applied in relapsed or refractory disease, if tolerable. Here, we retrospectively analyzed 59 patients with r/r PCNSL focusing specifically on differences in long-term outcome and toxicity in patients <65 years (n = 33) and ≥65 years (n = 26) of age. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is reportedly an effective treatment strategy in relapsed or refractory primary CNS lymphoma (r/r PCNSL); however, only selected patients are eligible for this treatment. We retrospectively analyzed outcome, prognostic factors, and toxicity in 59 patients with r/r PCNSL planned to receive HCT-ASCT at our institution between January 2005 and December 2021 (n = 33 < 65 years; n = 26 ≥ 65 years). Median follow-up was 65 months (95% CI 21–109). Median age was 63 years (range 29–76), median Karnofsky performance score (KPS) was 80 (range 30–100). In the entire cohort of 59 patients, median overall survival (OS) was 14 months (95% CI 0–37). In 50/59 (84.7%) patients who completed HCT-ASCT, median progression free survival (PFS) was 12 months (95% CI 3–21) and median OS 30 months (95% CI 0–87). 1-year, 2-year, and 5-year OS rates of 61.2%, 52.3% and 47.1%, respectively, were observed. Six patients (10.2%) died related to treatment (1 during induction treatment, 5 post HCT-ASCT). Age was not prognostic. On univariate analysis, KPS ≥ 80 (p = 0.019) and complete or partial remission before HCT-ASCT (p = 0.026) were positive prognosticators of OS; on multivariate analysis, KPS (p = 0.043) and male gender (p = 0.039) had an impact on OS. The 5-year OS rate in patients with progressive or stable disease after induction treatment was 32.7%. In summary, HCT-ASCT was effective and feasible in this cohort of r/r PCNSL patients. Clinical state, remission status before HCT-ASCT, and gender influenced survival, whereas age did not influence outcome in this study. [ABSTRACT FROM AUTHOR]