Rationale Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor in clinical development for the treatment of COPD and asthma. Patients with airway infections may be treated with erythromycin, thus, potential pharmacokinetic (PK) interactions of roflumilast and erythromycin were investigated. Methods In an open-label, 2-period study, 18 healthy male subjects received a single oral dose of 500 mg erythromycin in period 1. In period 2, oral roflumilast 500 μg was given once daily for 11 days with concomitant erythromycin 500 mg on Day 11. Blood samples were collected on Days 1, 10, and 11. Plasma concentrations of roflumilast, its pharmacodynamically active N-oxide metabolite, and erythromycin were measured. Results Point estimates and 90% confidence intervals for the Test/Reference ratios (Day 11/10) met predefined equivalence ranges for AUC0-24h (1.05; 1.01 - 1.10) and Cmax (0.96; 0.87 - 1.06) of roflumilast as well as for AUC0-24h (0.89; 0.87 - 0.92) and Cmax (0.83; 0.79 - 0.87) of roflumilast N-oxide. Co-administration of roflumilast, in steady state, modestly affected AUC0-inf (0.79; 0.70 - 0.90) and Cmax (0.81; 0.64 - 1.01) but not t1/2 of erythromycin. There were no clinically relevant changes in ECG or vital signs. Conclusions PK of roflumilast and roflumilast N-oxide was not influenced by co-administration of erythromycin. The small effect of roflumilast on erythromycin PK may not require dose adjustment. Co-administration of roflumilast and erythromycin as well as roflumilast alone were well tolerated.