Background: Prostate-specific membrane antigen (PSMA) is an ideal target for RLT in mCRPC patients (pts). Alpha-emitting radioisotope Actinium-225 (Ac-225) may be more efficacious than beta-emitting Lutetium-177, due to higher rates of double-strand DNA breaks in prostate cancer cells, with less tissue penetration and minimal bystander effects in PSMA-negative cells. Limited data is available on the clinical efficacy and side effects of PSMA-Ac-225 RLT in mCRPC pts. Here we describe our clinical experience so far. Methods: Between February 2016 and October 2017, 11 pts underwent PSMA-Ac-225 RLT in Heidelberg, Germany. Prostate-specific antigen (PSA) responses were measured every two weeks. Pts underwent PSMA PET/CT prior to and after RLT. Consenting pts had tissue and blood collected for translational biomarker studies, including targeted-next generation sequencing and whole genome sequencing to discover biomarkers and mechanisms of RLT resistance. In addition, pts received structured questionnaires on quality of life and xerostomia evaluation. Results: All pts were heavily pre-treated, with a median of four therapies prior to PSMA-Ac-225 RLT. Pts underwent a median of three RLT cycles (range 1-4 cycles) of median 8 MBq (range 6-10 MBq). Five pts (45%) had died at time of analysis. Median overall survival since start of RLT was 12.6 months (95% CI 5.0-20.1). Median baseline PSA was 878 µg/L (range 6-2249). Eight of eleven pts had > 50% PSA response, with median change in PSA reduction of 87%. Six pts were evaluable according to PCWG3 criteria with 5/6 (83%) pts showing partial responses, and one patient with stable disease following RLT. No grade 3-4 hematologic toxicity occurred. Grade 2-3 xerostomia was mentioned by all pts. Pts with features of neuro-endocrine prostate cancer (NEPC) showed less response to RLT, with blood-based NEPC biomarkers increasing during RLT. Conclusions: PSMA-Ac-225 RLT resulted in remarkable clinical, biochemical and radiological responses in end-stage mCRPC pts, and may be considered a promising therapy for mCRPC pts.