Purpose <p>Given the increasing inclusion of ECOG 3 patients in oncology practice, data on this subgroup in the context of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) remain limited. This study evaluates the safety and outcome of PSMA-RLT in metastatic castration-resistant prostate cancer (mCRPC) patients with ECOG performance status 3.</p> Methods <p>In this analysis, a cohort of 18 mCRPC patients with ECOG performance status 3 who received PSMA-RLT was examined. The median number of treatment cycles was 2 (range: 1–10), with a mean cumulative administered activity of 21.5 ± 15.0 GBq (range: 2.7–62.6 GBq) of [¹⁷⁷Lu]Lu-PSMA-617. Outcome and adverse events including hematologic and renal toxicities, fatigue, and xerostomia were analyzed.</p> Results <p>50% of patients achieved either stable disease or a partial biochemical response. Median progression-free survival and overall survival were 1.3 months and 2.8 months, respectively. Severe adverse events were uncommon, occurring in three patients: one developed grade 3 leukopenia, another experienced grade 3 thrombocytopenia, and one patient had pancytopenia of grade 3/4. No higher RLT-induced grade of renal toxicity and xerostomia were observed, whilst symptoms of fatigue improved in the cohort.</p> Conclusion <p>This study indicates that PSMA-RLT is a feasible and overall well-tolerated treatment for mCRPC ECOG 3 patients with manageable toxicity profile. Despite limited survival outcomes, ECOG 3 status may be considered not to be a categorical exclusion criterion for RLT. Future prospective studies should further investigate the role of PSMA-RLT in this challenging subgroup.</p>