Background: TACE is the most widely used locoregional therapy recommended for patients with intermediate-stage HCC (Barcelona Clinic Liver Cancer stage B). Despite the significant tumor responses that can be achieved with TACE, tumors commonly recur, progress, or are refractory. Clinical trials have explored the combination of TACE with tyrosine kinase inhibitors; however, these have not reported improved outcomes. HCC possesses a unique immunosuppressive microenvironment, which makes it an attractive target for immunotherapies, particularly immune checkpoint inhibitors. Furthermore, there is evidence that locoregional interventions induce changes in the immune environment that could promote synergy with checkpoint inhibitors. Preliminary data for the combination of TACE with nivolumab indicate an acceptable safety profile and promising efficacy (Harding et al. ASCO-GI 2020). NIVO monotherapy and NIVO+IPI combination therapy are both approved in the United States for patients with HCC previously treated with sorafenib. Together, these findings support investigation of TACE plus NIVO, IPI, or NIVO+IPI to address the therapeutic needs of patients with intermediate HCC. Methods: CheckMate 74W is a global, double-blind, placebo-controlled, 3-arm, randomized phase III trial. Patients with tumors that exceed the Beyond Milan and Up-to-7 criteria (7 being the sum of size [in centimeters] and number of tumors), eligible for TACE, with Eastern Cooperative Oncology Group performance status of 0 to 1 are eligible for enrollment. Patients must not have received prior locoregional therapies. Approximately 765 patients will be randomized in a 1:1:1 ratio to NIVO+IPI+TACE (arm A), NIVO+IPI placebo+TACE (arm B), or NIVO placebo+IPI placebo+TACE (arm C). Primary endpoints are the time to TACE progression (TTTP), assessed by blinded independent central review, and overall survival in arm A versus arm C. Secondary endpoints are TTTP and overall survival in arm B versus arm C, event-free survival, and progression-free survival. Clinical trial registry: NCT04340193. Clinical trial information: NCT04340193