OBJECTIVE The benefit of immune checkpoint inhibitors' (ICIs) combination therapy in patients with advanced esophageal squamous cell carcinoma (ESCC) remained unclear. We performed a meta-analysis to explore the efficacy and safety of ICIs' combination therapy versus chemotherapy alone as first-line treatment in advanced ESCC. METHODS A systematic review of randomized controlled trials (RCTs) of ICIs' combination therapy as first-line treatment in advanced ESCC was conducted via searching PubMed, Embase, and Cochrane database. The data for efficacy and safety of ICIs' combination therapy were subject to meta-analysis. Subgroup analysis was performed in patients with different PD-L1 expression status. RESULTS A total of 5 RCTs and 3163 patients were included. Overall, the hazard ratio (HR) for overall survival (OS) benefit with ICIs' combination therapy was 0.68 (95% CI 0.62-0.75) compared with chemotherapy alone. The HR for progression-free survival (PFS) benefit and the odds ratio (OR) for overall response rate (ORR) increase were 0.62 (95% CI 0.56-0.68) and 2.01 (95% CI 1.70-2.38), respectively. The OS and PFS benefits with ICIs' combination therapy over chemotherapy alone were also observed in the subgroup of PD-L1 positive expression, but not in the subgroup of PD-L1 negative expression. The incidence of grade 3 or higher treatment-related adverse events was 60.4% with ICIs' combination therapy and 56.3% with chemotherapy alone (OR, 1.19; 95% CI 0.90-1.57). CONCLUSIONS ICIs' combination therapy showed superior OS, PFS, and ORR over chemotherapy alone with a manageable safety profile. These results suggested that ICIs' combination therapy can be considered as a new first-line treatment for advanced ESCC.