Depression is the main psychiatric symptom in patients living with HIV. Genetic predisposition, stress from disease as well as the antiretroviral therapy itself are discussed as pathogenic factors. We report a 35-year-old HIV-positive man suffering from bipolar disorder who developed major depression shortly after commercing combination antiretroviral therapy (cART) on three occasions. The first two times the patient ceased therapy autonomously, and the depression disappeared completely. The close connection between cART and major depression in the present case supports the depression-inducing potential of cART. Additionally, we present an overview of literature.