Background and Objectives: Peritoneal metastasis from colorectal cancer carries a high risk for relapse after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). A novel alpha-emitting radiopharmaceutical (Radspherin) has been designed to deliver short-range radiation to micrometastases and free-floating tumor cells. Methods: A Phase 1/2a study evaluated the safety, tolerability, and signal of efficacy of escalating doses of Radspherin injected intraperitoneally after CRS-HIPEC. Results: Eleven patients received 1-4 MBq (Group 1) whereas 12 patients received 7 MBq; nine patients single dose/three patients split-dose (Group 2). Median age was 66.5 and 61.5 years, and median peritoneal cancer index 6 and 7, respectively. One hundred and seventy-eight adverse events were reported, only seven were deemed related to Radspherin. Thirteen serious adverse events (SAEs) were reported in eight patients and no SAEs were related to Radspherin. At 18-months, none of the 12 patients receiving 7 MBq experienced peritoneal recurrences, however four had non-peritoneal recurrences. Across both groups (n = 22), 41% had recurrent disease, only 14% of them in the peritoneum. Conclusions: Radspherin was well tolerated. At 18 months, median disease-free survival has not been reached, and none of the patients receiving the recommended dose (7 MBq) had peritoneal recurrences. The results are encouraging and warrant further clinical evaluation.