Background: Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, is currently in clinical development for the treatment of asthma. Objectives: This pilot study examined the effect of roflumilast on allergen-induced airway hyperresponsiveness (AHR) to histamine challenge and asthmatic response to allergen challenge. Methods: In a randomized, double-blind, 2-period, crossover trial, 13 patients with mild allergic asthma [mean forced expiratory volume in 1 s (FEV₁) % predicted = 86%] received a single dose of oral roflumilast 1,000 µg or placebo. Patients were administered roflumilast 60 min before allergen challenge, and asthmatic responses were assessed via change in FEV₁ ≤9 h after allergen challenge. AHR to histamine provocation was measured before and repeated 24 h after allergen provocation. Patients inhaled histamine in doubling concentrations until attaining a decrease in FEV₁ of ≤20% (PC₂₀FEV₁). Results: Roflumilast had no detectable bronchodilator activity 60 min after administration. Roflumilast significantly attenuated AHR compared with placebo, with a mean change in pre- to postallergen challenge PC₂₀FEV₁ ratio of 1.23 ± 2.75 and 2.51 ± 2.95 for roflumilast and placebo, respectively (p = 0.002). During the late asthmatic response, roflumilast reduced the mean maximum decrease in FEV₁ from 2 to 9 h after allergen challenge compared with placebo (p = 0.005). Additionally, FEV₁ at 9 h after challenge was significantly higher in patients treated with roflumilast (p = 0.03). Early asthmatic responses to allergen challenge were not significantly reduced by the single dose of roflumilast. Conclusions: Roflumilast attenuated allergen-induced AHR in patients with mild asthma. These results support further investigation of roflumilast as an anti-inflammatory treatment of asthma.