The pharmacokinetic interaction between sildenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, and ambrisentan, an ETA-selective, propanoic acid–based endothelin receptor antagonist (ERA), was studied in a 2-period crossover study in 19 healthy volunteers, with ambrisentan exposure (AUC0-∞) and maximum plasma concentration (Cmax) determined over 24 hours for a 10-mg dose of ambrisentan alone and again after 7 days of sildenafil 20 mg 3 times daily. The AUC0-∞ and Cmax for sildenafil and N-desmethyl sildenafil (active metabolite) were determined over 24 hours for a 20-mg dose of sildenafil alone and again after 7 days of dosing with ambrisentan 10 mg once daily. There was no clinically relevant pharmacokinetic interaction between ambrisentan and sildenafil or N-desmethyl sildenafil. Ambrisentan Cmax was unchanged (96.3% [90% confidence interval: 86.0%-107.8%]), with a minor increase in AUC0-∞ (108.5% [102.6%-111.7%]) with sildenafil coadministration. Sildenafil Cmax was increased slightly (113.4% [99.6%-129.1%]), and AUC0-∞ was unchanged (98.7% [91.2%-110.5%]) with ambrisentan coadministration. N-desmethyl sildenafil was unaltered. Dose adjustment of either drug is not necessary compared with administration alone.