Background: Atopic dermatitis (AD) is an inflammatory skin disease that presents with intense pruritus and red, inflamed lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, topical anti-inflammatory, phosphodiesterase 4 inhibitor for the treatment of AD. Objective: To evaluate the additional predefined efficacy endpoints on the impact of crisaborole ointment on pruritus and signs of AD from 2 Phase 3 studies (AD-301: NCT02118766; AD-302: NCT02118792). Methods: Patients ≥2 years old with mild-to-moderate AD were enrolled in 2 multicenter, double-blind, vehicle-controlled, identically designed Phase 3 studies. Patients were randomly assigned 2:1 for treatment with crisaborole or vehicle twice daily for 28 days. Exploratory efficacy endpoints evaluated severity of signs of AD (measured weekly: erythema, induration/papulation, exudation, excoriation, and lichenification) and pruritus (measured twice daily) on a 4-point scale (None [0] to Severe [3]). Achievement of None (0) or Mild (1) with ≥1-grade improvement from baseline defined Success for each sign or symptom. Time to Success in Pruritus was examined using Kaplan-Meier analysis. Results: Studies AD-301 and AD-302 enrolled 503:256 and 513:250 crisaborole:vehicle patients, respectively. Across treatment groups/studies, baseline severity of signs and symptoms was generally balanced. Success in Pruritus was achieved sooner by crisaborole-treated patients than vehicle-treated patients (pooled data: median 1.37 vs 1.70 days; P = 0.001). A greater proportion of crisaborole-treated patients achieved Success for all clinical signs of AD than vehicle-treated patients in both studies ([AD-301, crisaborole vs vehicle; AD-302, crisaborole vs vehicle] erythema: 62.8% vs 46.1%, 54.9% vs 33.9%; induration/papulation: 57.7% vs 54.8%, -51.9% vs 40.2%; exudation: 41.0% vs 33.3%, 38.1% vs 27.2%; excoriation: 63.0% vs 51.8%, 57.2% vs 44.2%; lichenification: 51.7% vs 46.5%, 51.4% vs 35.3%). Conclusion: Crisaborole Topical Ointment, 2%, demonstrated improvement in all measured signs of AD and early relief of pruritus in 2 large Phase 3 studies and may represent an efficacious and safe treatment for patients with mild to moderate AD as young as 2 years.