The purpose of this study is to evaluate the associations between gastroesophageal reflux disease (GERD) and depression using a national sample cohort of the Korean population. Data were collected from individuals ≥20 years old in the Korean National Health Insurance Service-National Sample Cohort between 2002 and 2013. We designed two different nested case-control studies. In study I, 60,957 participants with depression were matched at a 1:4 ratio with 243,828 controls, and their previous histories of GERD were analyzed. In study II, 133,089 participants with GERD were matched at a 1:2 ratio with 266,178 controls, and their previous histories of depression were analyzed. Crude and adjusted odds ratios (ORs) were analyzed using unconditional logistic regression analyses, and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed according to age and sex. The adjusted OR for GERD was 2.01 (95% CI = 1.96-2.07) in the patients with depression (study I). The adjusted OR for depression was 1.48 (95% CI = 1.43-1.52) in the patients with GERD (study II). The results of the subgroup analyses were consistent. GERD and depression displayed bidirectional associations.