BACKGROUND The aim of this study was to investigate the association between cyclooxygenase-2 (COX-2) rs689466 (-1195 G>A) polymorphism and susceptibility to head and neck squamous cell carcinoma (HNSCC) by performing a meta-analysis. MATERIAL AND METHODS PubMed and Embase were searched for relevant cohort and case-control studies up to 13 March 2015. After data extraction and methodological quality assessment for eligible studies, the overall, subgroup, sensitivity, and cumulative meta-analyses were conducted using the Comprehensive Meta-Analysis software (version 2.2). RESULTS Finally, 5 case-control studies involving 1564 HNSCC patients and 2346 healthy controls were included. For overall population, the results of 3 genetic models showed significant association, while the other 2 presented negative association [A vs. G: OR=0.97-1.09, 95%CI=0.97-1.09; AA vs. GG: OR=1.26, 95%CI=1.01-1.57; AA vs. GA: OR=1.21, 95%CI=1.01-1.45); AA vs. (GG+GA): OR=1.20, 95%CI=1.01-1.43; (AA+GA) vs. GG: OR=0.98, 95%CI=0.84-1.15]. Publication bias was not assessed due to the limited number of included studies. CONCLUSIONS This meta-analysis indicated that COX-2 rs689466 polymorphism might be associated with increased susceptibility to HNSCC. We also suggest performing more relevant studies in order to enlarge the sample size and obtain more precise results.