Background: Immune checkpoint inhibitors (ICIs) showed antitumor activity for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, the results from different studies were controversial.Methods: Online databases were searched for randomized clinical trials (RCTs) evaluating ICIs for R/M HNSCC. The characteristics of the studies and the results of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), treatment-related adverse events (TRAEs) were extracted.Results: A total of 4936 patients from eight studies were included. Anti-PD1/PDL1 monotherapy significantly improved OS in total population (hazard ratio, HR, 0.87, 95% CI, 0.79-0.95, p = 0.003) and PD-L1 high expression patients (HR, 0.71, 95% CI, 0.55-0.90, p = 0.006) with significant lower incidence of any grade TRAEs (odds ratio, OR, 0.16, 95% CI, 0.07-0.37, p < 0.00001) and Grades 3-5 TRAEs (OR, 0.18, 95% CI, 0.10-0.33, p < 0.0001) compared with standard of care (SOC); however, the pooled results of PFS and ORR were not significant different. PD1/PDL1 inhibitors plus CTLA4 inhibitors did not improve OS, PFS, ORR compared with SOC or ICIs monotherapy; however, the incidence of Grades 3-5 TRAEs was significant higher compared with ICIs monotherapy (OR, 1.80, 95% CI, 1.34-2.41, p = 0.0001).Conclusions: Anti-PD1/PDL1 monotherapy could improve OS for R/M HNSCC with significant lower incidence of TRAEs compared with SOC. PD1/PDL1 inhibitors plus CTLA4 inhibitors showed no more benefit compared with both SOC and ICIs monotherapy, but the incidence of Grades 3-5 TRAEs was significant higher compared with ICIs monotherapy.