The association between isotretinoin therapy and depressive symptoms in acne patients has generated much recent interest but has not been systematically explored. A 17-year-old man with acne vulgaris developed symptoms of acute depression two weeks after beginning isotretinoin therapy. The depressive symptoms improved with reduction of isotretnoin dose and treatment with sertraline. Of note, however, is that when the isotretinoin dose was again increased, the depressive symptoms recurred despite clearing of the skin, leading to an unsuccessful suicide attempt. Isotretinoin was finally discontinued and the depression rapidly resolved. Although the effects of hypervitaminosis A may be involved aetiologically, the predictive factors of drug-related depression remain unclear. Significant depressive symptoms that develop during the course of treatment need close monitoring and may necessitate both antidepressant therapy and discontinuation of the drug. Given the uncertain causal relationship between isotretinoin and depression, versus the potential psychological benefits of effective acne treatment, systematic studies exploring the impact of isotretinoin on mood are needed.