Oral isotretinoin is a highly effective agent for the treatment of moderate to severe acne, but ever since oral isotretinoin was introduced as a modality for acne, the relationship between oral isotretinoin therapy and psychiatric problems, especially depression, has been controversial. The purposes of this study were to know the acute effects of oral isotretinoin therapy on psychiatric symptoms and to investigate the relationships among them, which have not been reported in the published work. This cohort study included 38 acne patients who started oral isotretinoin therapy. Individual patients were examined before administering oral isotretinoin and 2 and 8 weeks after commencement. Acne severity was graded using the Leeds revised acne grading system. Acute psychiatric effects of oral isotretinoin were assessed using a questionnaire authorized by two psychiatrists. This questionnaire included assessments of acne-related quality of life (Assessment of the Psychological and Social Effects of Acne [APSEA]), depression (Beck's depression inventory [BDI]), anxiety (Beck's anxiety inventory [BAI]) and psychopathology (Symptomchecklist-90-revised [SCL-90-R]). Acne grading and APSEA showed similar change patterns. Both improved after 8 weeks of oral isotretinoin treatment. On the other hand, the severity of depression decreased after 2 weeks of treatment. A significant correlation was found between BDI and APSEA, but no correlation was found between BDI and acne grade. These results indicate that oral isotretinoin therapy alleviates depressive symptoms. Improvements in depression are directly related to acne-related life quality improvements rather than to improvement in acne grade.