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Objective: Tumor necrosis factor inhibitors (anti-TNF) have become the standard treatment for rheumatoid arthritis (RA). However, evidence is inconsistent as to whether RA patients with anti-TNF are associated with an increased risk of non-melanoma skin cancer (NMSC) compared with those without anti-TNF. We performed a systematic review and meta-analysis to evaluate the risk of NMSC in patients with anti-TNF drugs compared with those without anti-TNF. Methods: We did a systematic literature search with PubMed, EMBASE, and the Cochrane Library from inception to April 1, 2019. Prospective observational studies were eligible for inclusion if they included any of the approved anti-TNF drugs and reported the risk estimates and 95% confidence interval (95% CI) of NMSC associated with anti-TNF in RA patients. Pooled relative risks (RRs) and 95% CIs were calculated using a fixed-effects model. To assess the heterogeneity and risk of publication bias, we respectively conducted the subgroup and sensitivity analysis, funnel plot, Begg's and Egger's test. Results: The present meta-analysis included six studies with 123,031 patients. Compared with RA patients without anti-TNF, patients with anti-TNF drugs were associated with an increased risk of NMSC (RR 1.28, 95% CI 1.19 to 1.38; I2 = 45.6%, P = 0.056), especially squamous cell skin cancer (SCC) (RR 1.30, 95% CI 1.09 to 1.54; I2 = 0%, P = 0.854), but not basal cell skin cancer (RR 1.13, 95% CI 0.97 to 1.31; I2 = 0%, P = 0.555). Sensitivity and subgroup analysis confirmed the robustness of the primacy results. There was no evidence of publication bias with Begg's and Egger's test or by inspection of the funnel plot. Conclusions: These results suggest that RA patients treated with anti-TNF are at an increased risk of NMSC, especially SCC. However, this association in RA urgently needs the more clinical studies and basic researches to further validate. Key Points • Rheumatoid arthritis patients treated with tumor necrosis factor inhibitors are associated with a higher risk of non-melanoma skin cancer compared to those patients treated without tumor necrosis factor inhibitors. Hence, tumor necrosis factor inhibitors may be avoided in rheumatoid arthritis patients who are at high risk of non-melanoma skin cancer. • Of note, rheumatoid arthritis patients who were treated for tumor necrosis factor inhibitors compared with patients who were not treated for tumor necrosis factor inhibitors were at significantly increased risk of squamous cell skin cancer, but were not at increased risk of basal cell skin cancer. Therefore, use of tumor necrosis factor inhibitors in rheumatoid arthritis patients should be paid attention to the occurrence of squamous cell skin cancer. [ABSTRACT FROM AUTHOR]