Abstract Background Patients with metastatic clear cell renal cell carcinoma (ccRCC) have a dismal prognosis. Therefore, new and less toxic treatments are needed. Objective We determined the maximum tolerated dose (MTD) and potential therapeutic efficacy of multiple infusions of lutetium 177 (177 Lu)-girentuximab (cG250) on various dose levels in a phase 1 trial in patients with progressive metastasized ccRCC. Design, setting, and participants In this uncontrolled case series in 23 patients with progressive ccRCC metastases, cG250 accumulation was verified by diagnostic indium 111-cG250 imaging. Patients then received a high-activity dose of177 Lu-cG250. Intervention Groups of three patients received177 Lu-cG250, starting at a dose level of 1110 MBq/m2177 Lu-cG250, with dose increments of 370 MBq/m2 per group. In the absence of persistent toxicity, progressive disease, and accelerated blood clearance, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. Patients could receive a total of three treatment cycles. Outcome measurements and statistical analysis Determination of the MTD was the primary and therapeutic efficacy was the secondary outcome measurement of the study. Results and limitations The MTD was 2405 MBq/m2 because higher doses resulted in dose-limiting myelotoxicity. Some patients received second (13 of 23 56%) and third (4 of 23 17%) treatment cycles. Most patients (17 of 23 74%) demonstrated stable disease 3 mo after the first treatment, and one patient showed a partial response that lasted for 9 mo. Mean growth of target tumor lesions was reduced from 40.4% (95% confidence interval CI, ±17.0) during the last 3 mo before study entry to 5.5% (95% CI, ±5.3; p < 0.001) at 3 mo after the first treatment cycle. No major nonhematologic side effects were observed. Conclusions177 Lu-cG250 radioimmunotherapy in metastatic ccRCC patients is well tolerated at an activity dose level as high as 2405 MBq/m2 (MTD). Radioimmunotherapy with177 Lu-cG250 may stabilize previously progressive metastatic ccRCC.