Background: RT causes immunologic effects that enhance the efficacy of immune checkpoint blockade in preclinical models. No prospective clinical trial data exist for the safety and efficacy of combining RT with the nivo + ipi combination. Methods: We conducted a prospective study (NCT02659540) where patients with metastatic melanoma were treated with nivo (1 mg/kg) + ipi (3 mg/kg) every 3 weeks (Q3W) for up to 4 doses, with optional nivo maintenance Q2W per standard of care. Following the first nivo + ipi dose, patients were treated with conventionally fractionated RT (30 Gy in 10 fractions) to one melanoma metastasis. Treatment-related (TRAE) and treatment-emergent (TEAE, all causality) adverse events within the first 24 weeks of immunotherapy initiation were summarized overall and by CTCAE grade. Objective response rate (ORR) was assessed by RECIST 1.1 outside and within the irradiated fields. ORR rates were provided with binomial 95% confidence intervals (CI). Results: Ten patients (median age: 65 [range: 28-86] years; 6 female) received at least 1 dose of study therapy and were included in the safety analyses. One patient withdrew consent prior to efficacy assessment and was excluded from efficacy analyses. All patients had ≥1 any grade (G) TEAE. G3/4 TRAE occurred in 4 patients (40%), and G3/4 TEAE occurred in 7 patients (70%). G3/4 TRAE were anemia, thrombocytopenia, increased lipase, and pruritus. ORR outside of the irradiated field was 44% (4/9, 95% CI: 14-79%). Responses were also seen within the irradiated fields. Two patients died due to disease progression. Conclusions: This first prospective study in a small group of patients suggests it is safe to combine conventionally fractionated RT with nivo + ipi. Based on acceptable G3/4 TRAE in this fully accrued cohort testing conventionally fractionated RT, accrual is ongoing to a second cohort where patients receive higher dose per fraction RT with nivo + ipi. Clinical trial information: NCT02659540