The aim of this evaluation is to identify first indicators regarding the efficacy of 225Ac-PSMA-617 therapy in a retrospectively analyzed group of patients. Methods: Forty patients with metastatic castration-resistant prostate cancer were selected for treatment with 3 cycles of 100 kBq/kgBW 225Ac-PSMA-617 in 2 months intervals. Prostate-specific antigen (PSA) and blood cell count were measured every 4 weeks. Prostate-specific membrane antigen (PSMA)-PET/CT or PSMA-SPECT/CT were used for baseline staging and imaging follow-up at month six. Follow-up included duration of PSA-response and radiological progression free survival at month six. Patient histories were reviewed for the duration of previous treatment lines and a Swimmer-Plot was used to intra-individually compare the duration of tumor control by PSMA-therapy vs. prior treatment modalities. Results: 31 of 40 patients were treated per protocol. 5 patients discontinued due to non-response, 4 patients due to xerostomia. In patients surviving at least eight weeks, a PSA decline >50% was observed in 24/38 (63%) and any PSA response in 33/38 (87%) of patients. Median duration of tumor-control under 225Ac-PSMA-617 last-line therapy was 9.0 months; 5 patients presented with enduring responses of > 2 years. As all patients had very advanced disease this compares favorably with the tumor-control rates associated with earlier phase disease; the most common preceding 1st, 2nd, 3rd and 4th line therapies were abiraterone (median duration 10.0 months), docetaxel (6.5 months), enzalutamide (6.5 months) and cabazitaxel (6.0 months). Conclusion: Positive response of surrogate parameters demonstrates remarkable anti-tumor activity of 225Actinium-PSMA-617. Swimmer-plot analysis indicates promising duration of tumor-control, especially taking into account the unfavorable prognostic profile of the selected advanced-stage patients. Xerostomia was the main reason to discontinue therapy or to refuse additional administrations and was in the same dimension as non-response; this indicates that further modifications of the treatment regimen with regard to side effects might be necessary to further enhance the therapeutic range.