Benzoyl peroxide (BP) is among the most commonly prescribed topical treatments for acne vulgaris. To improve tolerability without adversely affecting efficacy, a novel formulation of 5.5% BP incorporated into synthetic polymer microspheres was developed. We conducted a pilot study comparing the efficacy and tolerability of this microsphere formulation to a leading formulation of 6% BP gel. Forty-eight subjects at 2 research facilities were enrolled in a 12-week study. Subjects were required to have mild to moderate facial acne vulgaris with defined lesion counts and were randomized and blinded to receive either the 5.5% BP microsphere formulation or 6% BP gel for the entire study. Efficacy was measured using acne lesion counts, along with static scoring of acne severity and a global improvement score. Tolerability was determined by collecting adverse event reports during the study, as well as scoring local skin reactions. Subject satisfaction was measured by survey questionnaires. Of the 48 subjects enrolled, 44 completed the study. One subject withdrew because of excessive irritation; all others tolerated the products well, experiencing infrequent (usually mild) redness, scaling, or dryness. The 5.5% microsphere formulation demonstrated a trend toward improved efficacy and tolerability compared with the 6% gel formulation. On average, subjects in the 5.5% microsphere formulation group showed substantially greater improvement in acne severity scores at each visit. Subject questionnaires demonstrated a preference for the 5.5% microsphere formulation because of perceived efficacy and cosmetic acceptance. BP products continue to be useful in the management of acne. The irritation profile of BP products may limit their use or force a choice to a lower-strength product. This study demonstrates that 5.5% BP incorporated into synthetic polymer microspheres has a tolerability profile equivalent to or better than a traditional 6% gel formulation, with greater efficacy and higher patient preference.