We describe a 44-year-old male patient with human immunodeficiency virus (HIV) infection and pulmonary arterial hypertension who was treated with several protease inhibitors and with sildenafil. In order to guide treatment with sildenafil, the pharmacokinetics and dynamics of sildenafil were monitored at various time points. In comparison with healthy subjects, the maximal concentration in plasma (Cmax), area under the curve (AUC), and elimination half-life of sildenafil were approximately doubled in the patient. After increasing the sildenafil dose to ensure therapeutic drug levels over 24 hours, the pulmonary arterial hypertension and physical performance of the patient improved significantly. We conclude that the elimination of sildenafil is impaired in patients treated with protease inhibitors, but to a lesser extent than predicted from single-dose studies reported in the literature. Patients treated concomitantly with protease inhibitors and sildenafil need close monitoring of plasma levels, pharmacodynamics, and toxicity of sildenafil in order to be treated optimally.