There have been recent concerns about the possible association between isotretinoin therapy and depressive symptoms. We conducted a prospective study to evaluate depressive symptoms and quality of life in acne patients having either isotretinoin or antibiotics/topical treatments. There were 215 patients (mean age 20 years) included in the study. Depression, quality of life and acne severity ratings were administered at baseline, 1 month, 3 months and end of treatment or 6 months, and compared between both treatment groups. The changes in the mean depression scores did not differ significantly between both groups (P = 0.62). The incidence of isotretinoin patients with moderate depressive symptoms remained relatively unchanged from baseline. The changes in the quality-of-life measures scores between treatment groups showed no significant difference. No correlation between isotretinoin dose and depression score was found. Although five isotretinoin patients were withdrawn during the study because of worsening of mood, no definite causal relationship was established. This pilot study does not appear to support any direct link between depression and isotretinoin, apart from being a rare unpredictable idiosyncratic side-effect. However, because of the study limitations, a larger study is needed to confirm the findings.