BackgroundImmune checkpoint inhibitors (ICIs) are widely used in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC); however, the toxicity profiles are inconclusive.MethodsClinical trials evaluating ICIs for R/M HNSCC were searched from online databases. The characteristics of the studies and the results of incidences of any grade treatment-related adverse events (trAEs), grade three or more trAEs, treatment-related deaths, trAEs leading to discontinuation of treatment, and specific trAEs were extracted.ResultsTwenty studies with 3756 patients were included. The pooled incidences of any grade trAEs, grade three or more trAEs, treatment-related deaths, trAEs leading to discontinuation of treatment for overall population were 62.07% (95% CI, 59.07%-65.02%), 13.82% (95% CI, 11.23%-16.62%), 0.39% (95% CI, 0.15%-0.71%), 3.99% (95% CI, 2.36%-5.95%), respectively. Programmed cell death protein 1 (PD-1) inhibitors monotherapy and ICIs combination therapy had significantly higher incidences of any grade trAEs (odds ratio [OR], 1.25, 95% CI, 1.05-1.49 and 1.36, 95% CI, 1.15-1.60, respectively), grade three or more trAEs (OR, 1.41, 95% CI, 1.08-1.84 and 1.79, 95% CI, 1.39-2.30, respectively), trAEs leading to discontinuation of treatment (OR, 3.98, 95% CI, 2.06-7.70 and 10.14, 95% CI, 5.49-18.70, respectively) compared with programmed death-ligand 1 (PD-L1) inhibitors monotherapy. ICIs combination therapy had a significantly higher incidence of grade three or more trAEs compared with PD-1 inhibitors monotherapy (OR, 1.27, 95% CI, 1.03-1.55); however, the incidences of any grade trAEs and trAEs leading to discontinuation of treatment were not significant different.ConclusionsOur study suggests that the incidences of grade three or more trAEs, treatment-related deaths, and trAEs leading to discontinuation of treatment are low in R/M HNSCC patients treated with ICIs. PD-L1 inhibitors monotherapy may be safer compared with PD-1 inhibitors monotherapy and ICIs combination therapy.