Background <p>Lutetium-177 (¹⁷⁷Lu)-PSMA-617, a targeted radioligand therapy, has demonstrated significant survival benefits in patients with metastatic castration-resistant prostate cancer (mCRPC). Its application in patients with a superscan pattern, indicative of extensive skeletal metastases, is less studied due to concerns about hematologic toxicity from bone marrow involvement.</p> Methods <p>This study analyzed 133 mCRPC patients treated with ¹⁷⁷Lu-PSMA-617, divided into Superscan and Non-superscan groups. PSA response (≥ 50% decline), PSA progression free survival (PFS), overall survival (OS), and treatment safety were assessed.</p> Results <p>Among 133 patients, 17 (12.8%) exhibited a superscan pattern. The overall PSA response rate was 45.8%, (47.0% in the superscan group versus 45.6% in the non-superscan group; <i>p</i> = 0.485). Median PSA PFS was 8 months overall (95% CI: 5.5–10.4), with 4 months (95% CI: &lt;1–10.5) in the superscan group and 8 months (95% CI: 5.6–10.3) in the non-superscan group (<i>p</i> = 0.311). Median OS was 13 months overall (95% CI: 8.6–17.3), with 6 months (95% CI: &lt;1–18.7) in the superscan group and 14 months (95% CI: 9.3–18.6) in the non-superscan group (<i>p</i> = 0.052). Significant but manageable decreases were seen in platelet (PLT) and Alkaline phosphatase (ALP), and no significant changes in Hemoglobin (Hb), white blood cells (WBC), Lactate dehydrogenase (LDH), or creatinine, with no differences between superscan and non-superscan groups. Baseline hemoglobin was a significant predictor of OS (HR = 0.6, <i>p</i> = 0.001), while superscan pattern did not show statistical differences (HR = 1.0, <i>p</i> = 0.949).</p> Conclusion <p>This retrospective study suggests that ¹⁷⁷Lu-PSMA-617 is a feasible and safe radioligand therapy for mCRPC patients with a superscan pattern, showing comparable PSA response rates to non-superscan patients.</p>