Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects children and adults. Hallmarks of AD include pruritus and pruritus-induced scratching, which can lead to exacerbation of symptoms and worsening of disease. Objective: To assess the pooled efficacy, safety, and early relief of pruritus from two Phase 3 studies evaluating crisaborole ointment, an anti-inflammatory phosphodiesterase 4 inhibitor, in patients with mild to moderate AD. Methods: Two identically designed Phase 3 studies randomly assigned patients ≥2 years old with AD 2:1 to receive crisaborole or vehicle twice daily for 28 days. The primary endpoint defined success in the Investigator’s Static Global Assessment (ISGA), a 5-point scale (clear [0] to severe [4]), as clear (0) or almost clear (1), with ≥2-grade improvement from baseline (BL) at day 29. Secondary endpoints included the proportion of patients who achieved an ISGA score of clear (0) or almost clear (1). Post hoc analysis defined early improvement in pruritus, analyzed with a 4-point scale (none [0] to severe [3]), as none (0) or mild (1), with ≥1-grade improvement from BL at day 6. Results: Significantly more crisaborole- than vehicle-treated patients achieved success in ISGA (day 29: 32.1% vs 21.8%; P < 0.001). Additionally, significantly more crisaborole-treated patients achieved an ISGA score of clear or almost clear at day 29 (50% vs 35.2%; P < 0.001) and early improvement in pruritus (56.6% vs 39.5%; P < 0.001). Crisaborole-treated patients who attained early improvement in pruritus were significantly more likely to have success in ISGA (odds ratio [OR], 1.821; 95% confidence interval [CI], 1.119-2.965; P=0.016) and to achieve an ISGA score of clear or almost clear at day 29 (OR, 1.960; 95% CI, 1.335-2.879; P < 0.001). The most frequently reported treatment-emergent adverse events were application site pain (4.4% vs 1.2%) and upper respiratory tract infection (3.0% vs 3.0%). Conclusions: A greater proportion of crisaborole-treated patients than vehicle-treated patients demonstrated improvement in global disease severity and early relief of pruritus (day 6) while also demonstrating tolerable safety with crisaborole.