Psoriasis has a major impact on health-related quality of life. The present cohort study investigated the use of antidepressant drugs in psoriasis patients and a reference cohort, using pharmacy and hospitalization data from 1998 to 2008 for more than 2.5 million Dutch residents. Multivariate Cox regression was used to compare the risk of first antidepressant use, and Poisson regression to compare the number of episodes of antidepressant use. A total of 25,691 psoriasis cases and 128,573 reference subjects were followed for more than 9 years. The incidence of first antidepressant use was 21 and 9 per 1,000 person years, respectively, and the adjusted hazard ratio (HR) was 1.55 (95% confidence interval (CI) 1.50-1.61). Within the psoriasis cohort, the HR of receiving an antidepressant was significantly higher after the first antipsoriatic treatment (HR 1.07, 95% CI 1.02-1.12). Psoriasis patients have a two-fold increase in antidepressant use, the period after antipsoriatic treatment being characterized by a further increase in antidepressant drug dispenses.