Acne is the most common skin disease and isotretinoin is the most powerful drug among the various drugs used for its treatment, but it has some adverse effects. The aim of this study was to evaluate the effect of isotretinoin on depression and quality of life of a group of patients undergoing isotretinoin therapy before and after the treatment course.In this prospective study, 98 patients with severe acne were enrolled consecutively and underwent isotretinoin therapy receiving 0.5 mg/kg/d of isotretinoin for 16 weeks. Isotretinoin effects on quality of life and depression were evaluated using Dermatology Life Quality Index (DLQI) and Beck Depression Inventory (BDI) questionnaires, respectively.In this study, 98 patients suffering from severe acne (38 males and 60 females) were enrolled. Treatment of acne was associated with improvement of quality of life scores in both male and female patients (p = 0.001). Considering the cutoff value of 13 for mild depressive mood in the BDI score, in total, 48 (49%) of the enrolled patients (21 males and 33 females) had a mild depressive mood before the commencement of the treatment in this study. The analysis of before and after treatment BDI scores showed that the number of patients and also the mean score of BDI were increased in both male and female patients after the treatment (p<0.05).Isotretinoin therapy improved the quality of life of patients suffering from acne, but depression was accentuated in the patients to some extent.