Background: In March 2022, the US Food and Drug Administration approved ¹⁷⁷Lu-PSMA-617 for the treatment of patients with prostate-specific membrane antigen (PSMA) positive metastatic castration resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. This real-world study aims to describe clinical characteristics, treatment use, clinical outcomes in patients treated with ¹⁷⁷Lu-PSMA-617 in a growing US dataset. Methods: Adults (≥18 years) with ≥1 claim for ¹⁷⁷Lu-PSMA-617 between 3/01/22 and 6/30/2023 in the IQVIA open-source pharmacy and medical claims databases were retrospectively identified and included in this analysis. Clinical characteristics and treatment use, including prior treatment exposures, were derived from this cohort. A subset of these patients with available PSA results were assessed for PSA response after initiation of ¹⁷⁷Lu-PSMA-617. Baseline PSA was defined as the closest PSA value within 90 days prior to or on the first ¹⁷⁷Lu-PSMA-617 claim (index date). Post-treatment PSA response was defined as the lowest PSA value ≥28 days after the index date. The proportion of patients with ≥ 50%, ≥80% and ≥90% PSA reductions were reported. Results: A total of 1,710 patients treated with ¹⁷⁷Lu-PSMA-617, with mean (standard deviation) age was 72.2 (8.5) years, met eligibility and were included in the study. Common comorbidities included hypertension (34.7%), osteoarthritis (27.3%) and dyslipidemia (23.9%). Based on ICD-10 codes, 1,447 (84.6%) patients had bone metastases, and 575 (33.6%) had visceral metastases, of whom 128 (7.5%) had liver metastases. Only 59 (3.5%) patients had lymph node only metastasis. In the pre-index period, 83.4% patients had used prior ARPI and/or taxane chemotherapy, and 98% patients had used other systemic therapies. In a sub-analysis of 159 (9.3%) patients with pre- and post-index PSA values available (whose clinical characteristics are comparable to the overall cohort of 1,710 patients), median PSA at baseline before initiation of ¹⁷⁷Lu-PSMA-617 was 61 ng/ml. Among these patients, 53.5%, 29.6% and 22.6% had PSA reductions of ≥50%, ≥80% and ≥90%, respectively, while on treatment. Rate of PSA response was similar regardless of history of ARPI or taxane use. Conclusions: To our knowledge, this is the first large-scale report of real-world US patients treated with ¹⁷⁷Lu-PSMA-617. Clinical characteristics and PSA responses observed are consistent with results from the VISION clinical trial demonstrating benefit with ¹⁷⁷Lu-PSMA-617 treatment. Subsequent analysis with longer follow up are needed to understand the long-term outcomes associated with ¹⁷⁷Lu-PSMA-617 in real-world US patients.