Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792). Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P=.038; AD-302: 31.4% vs 18.0%, P<.001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P=.005; 48.5% vs 29.7%, P<.001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P≤.001). Treatment-related adverse events were infrequent and mild to moderate in severity. Short study duration was a limitation. Crisaborole demonstrated a favorable safety profile and improvement in all measures ofefficacy, including overall disease severity, pruritus, and other signs of AD.