Background Obstructive sleep apnea (OSA) has shown to be associated with an increased risk of atrial fibrillation in observational studies. Whether this association reflect causal effect is still unclear. The aim of this study was to evaluate the causal effect of OSA on atrial fibrillation. Methods and Results We used a 2-sample Mendelian randomization (MR) method to evaluate the causal effect of OSA on atrial fibrillation. Summary data on genetic variant-OSA association were obtained from a recently published genome-wide association studies with up to 217 955 individuals and data on variant-atrial fibrillation association from another genome-wide association study with up to 1 030 836 individuals. Effect estimates were evaluated using inverse-variance weighted method. Other MR analyses, including penalized inverse-variance weighted, penalized robust inverse-variance weighted, MR-Egger, simple median, weighted median, weighted mode-based estimate and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods were performed in sensitivity analyses. The MR analyses in both the fixed-effect and random-effect inverse-variance weighted models showed that genetically predicted OSA was associated with an increased risk of atrial fibrillation (odds ratio [OR], 1.21; 95% CI, 1.12-1.31, <0.001; OR, 1.21; 95% CI, 1.11-1.32, <0.001) using 5 single nucleotide polymorphisms as the instruments. MR-Egger indicated no evidence of genetic pleiotropy (intercept, -0.014; 95% CI, -0.033 to 0.005, =0.14). Results were robust using other MR methods in sensitivity analyses. Conclusions This MR analysis found that genetically predicted OSA had causal effect on an increased risk of atrial fibrillation.