The association between cholelithiasis and depression remains unclear. We examined the risk of depression in patients with cholelithiasis. From the National Health Insurance population claims data of Taiwan, we identified 14071 newly diagnosed cholelithiasis patients (4969 symptomatic and 9102 asymptomatic) from 2000 to 2010. For each cholelithiasis patient, 4 persons without cholelithiasis were randomly selected in the control cohort from the general population frequency matched by age, sex, and diagnosis year. Both cohorts were followed up until the end of 2011 to monitor the occurrence of depression. Adjusted hazard ratios (aHRs) of depression were estimated using the Cox proportional hazards model after controlling for age, sex and comorbidities. The overall incidence rates of depression were 1.87- and 1.83-fold greater in the symptomatic and asymptomatic cholelithiasis subcohorts than in the control cohort (incidence, 10.1 and 9.96 vs 5.43 per 1000 person-years, respectively). The multivariable Cox proportional hazards regression analysis revealed higher variable-specific aHRs in women than in men, in younger patients than in older patients, and in those without comorbidities than in those with any comorbidity. Cholecystectomy reduced the hazard of developing depression with aHRs of 0.79 (95% confidence interval [CI] 0.62-0.99) for symptomatic cholelithiasis patients and 0.76 (95% CI 0.60-0.96) for asymptomatic patients. Patients with cholelithiasis are at a higher risk of developing depression than the general population. Patients could be benefited from cholecystectomy and have the hazard of developing depression significantly reduced.