The relationship between non-steroidal anti-inflammatory drug (NSAID) use and esophageal squamous cell carcinoma (ESCC) has remained unclear. To evaluate the relationship between NSAID use and risk of ESCC, we searched the MEDLINE, Biosis, Web of Science and ISI proceedings databases up to September 2010, together with a manual search of reference lists of relevant articles. Studies evaluating the association between exposure to NSAIDs and risk of ESCC were included. The analyses used random-effect or fixed-effect model based on homogeneity analysis. Seven studies (six case-control studies and one nested case-control study) were included in this meta-analysis. NSAID use was associated with a reduced risk of ESCC (odds ratio = 0.58, 95% confidence interval = 0.47 to 0.72). Specific analysis for aspirin and non-aspirin NSAIDs yielded similar results. There was a protective association between NSAIDs and ESCC. This finding warrants more prospective studies evaluating the relationship between NSAIDs and ESCC.