OBJECTIVES:  The goal of this study was to analyze the impact of comorbidities on the cost of antidepressant drug therapy in patients with depression treated in German general practices (GPs). METHODS: The present study included 31,741 patients diagnosed with depression and treated with antidepressant drugs in 2015. Demographic data included age, gender, and type of health insurance coverage. Twenty comorbidities were included. The study sample was stratified by age, gender, type of health insurance coverage, type of comorbidity, and number of comorbidities. The annual antidepressant treatment cost per patient was calculated based on pharmacy sale prices. The multivariate regression analysis was fitted to estimate the adjusted treatment cost differences. RESULTS: The annual cost of antidepressant drugs was €107 in the population. It was similar in men and in women (difference of €1) but was significantly higher in individuals with private health insurance coverage than in people with public health insurance coverage (difference of €63). The annual cost increased with age, from €85 in patients aged 40 years or younger to €116 in patients aged between 61 and 70 years (difference of €11), and with the number of comorbidities, from €78 when there was no comorbidity to €134 when there were more than 5 comorbidities (difference of €57). CONCLUSIONS:  The cost of antidepressant treatment in Germany increased with the number of comorbidities.