This single-center, investigator-blinded, randomized, split-face, phase 4 study compared the irritation potential of tretinoin gel microsphere (TGM) 0.04% in a pump dispenser with adapalene 0.1% plus benzoyl peroxide 2.5% gel (ADA-BPO 0.1%/2.5%) in a panel of 170 subjects. Participants were treated with TGM 0.04% pump on a randomly assigned side of the face and ADA-BPO 0.1%/2.5% gel on the other side of the face daily for three consecutive weeks. Expert grader assessments of erythema and dryness and subject self-assessments of burning/stinging and itching were conducted daily, except on weekends. TGM 0.04% pump was associated with better facial tolerance as demonstrated by significantly less cumulative erythema (P < 0.0001), dryness (P < 0.0001), burning/stinging (P < 0.0001) and itching (P < 0.0001) compared with ADA-BPO 0.1%/2.5% gel. While both agents were well tolerated by most patients, TGM 0.04% pump demonstrated significantly better tolerance than ADA-BPO 0.1%/2.5% gel in both neurosensory parameters and signs of contact irritation.