Stage IIB/IIC melanoma has a high risk of recurrence after surgical resection. While, for decades, surgery was the only option for high-risk stage II disease in most countries, adjuvant therapies now exist. Anti-programmed cell death protein 1 (PD-1) antibodies significantly improve recurrence-free survival versus placebo in patients with fully resected stage IIB/IIC melanoma. Combined BRAF MEK inhibitor therapy showed benefits in high-risk stage III and advanced disease; however, its role in patients with fully resected stage BRAF-mutated IIB/IIC melanoma is still unknown. Here we describe the rationale and design of the ongoing randomized, placebo-controlled COLUMBUS-AD trial, the first study of a BRAF-MEK inhibitor combination therapy (encorafenib + binimetinib) in patients with BRAF V600-mutated stage IIB/IIC melanoma.