Benzoyl peroxide (BPO) is a cornerstone of acne therapy, often used in combination with a topical antibiotic and/or a retinoid. Three independent 2-week studies were conducted in healthy subjects to compare the tolerability and irritation potential of topical treatment with Duac® Gel (BPO 5%-clindamycin phosphate 1.2%) vs Acanya® Gel (BPO 2.5%-clindamycin phosphate 1.2%), Aczone® Gel (dapsone 5%), or Epiduo® Gel (BPO 2.5%-adapalene 0.1%). For each study, subjects were randomized to apply one of the comparative products on one side of the face; the contralateral side remained untreated. Primary (erythema and dryness) and secondary tolerability assessments were performed throughout the study. Independent blinded expert grader assessments of erythema found no significant overall difference between any of the comparative groups. Treatment with Epiduo Gel resulted in a significant increase in dryness and evaporative water loss values compared with Duac Gel. Overall, subject self-assessments were equally favorable across all study groups, although the Epiduo Gel group reported a higher frequency of adverse perceptions (ie mild burning/stinging). In conclusion, the four topical acne medications tested were well tolerated throughout the study period. Treatment with Epiduo Gel resulted in a significant increase in dryness, evaporative water loss, and sensations of burning and stinging. No other significant differences in self-assessment perceptions were observed between treatments.