The Dermatology-specific Quality of Life (DSQL) instrument is a new tool which has been developed to address the effects of skin disease and its treatment on physical and social functioning and self-perceptions. Previous reports have demonstrated its cross-sectional validity. The current study examines the DSQL's responsiveness to 12 weeks of acne treatment in a placebo-controlled randomized clinical trial. The DSQL change scores were moderately correlated (r = 0.18 to 0.37) with treatment efficacy parameters including: dermatologist's rating of improvement of acne and a skin irritation score, and highly correlated with patient's global rating of acne severity. Within treatment groups, the DSQL discriminated clinically meaningful changes associated with small and moderate effect sizes. The DSQL total score showed statistically significant differences on nearly all comparisons with placebo. The DSQL dimension scores were sensitive to the most effective therapy compared to placebo. Responsiveness benchmarks are provided for small and moderatesized treatment effects. As a comprehensive instrument, the DSQL is a practical and psychometrically sound tool for use in clinical trials in dermatology.