Background: Patients with microsatellite stable (MSS), BRAF^V600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with a reported overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAF^V600E mCRC. In preclinical models of MSS, BRAF^V600E CRC, inhibition of BRAF and EGFR induces a loss of expression of mismatch repair genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAF^V600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAF^V600E mCRC. Methods: In this prospective phase II clinical trial (N = 75), patients with previously treated MSS, BRAF^V600E mCRC will be randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients will receive E (300 mg PO daily) and C (500 mg/m² IV every 14 days), and patients in the experimental arm will receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α = .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months and a hazard ratio of 0.57. Additional patient specimens will be collected for exploratory correlative research. The study activated across the United States in June 2022 and as of September 2022 has enrolled 2 of 75 planned participants. Funding: NIH/National Cancer Institute grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by The Hope Foundation for Cancer Research STrS award. Clinical trial information: NCT05308446.