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 repairs 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 participants 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 PFS for participants with MSS, BRAF^V600E mCRC. Methods: In this prospective phase II clinical trial (N=75), participants 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 participants will receive E (300 mg PO daily) and C (500 mg/m² IV every 14 days), and participants 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 participants specimens will be collected for exploratory correlative research. As of 9/2023, 37 of 75 planned participants have been enrolled. Clinical trial information: NCT05308446.