To determine the effects of tadalafil on the cardiovascular system, safety assessments were performed on a database of >4000 subjects who received tadalafil in >60 clinical pharmacology, phase 2, phase 3, and open-label studies. In healthy subjects, tadalafil resulted in small changes in blood pressure, which are not believed to be clinically relevant. Daily administration of tadalafil 20 mg for 26 weeks in healthy male subjects or patients with mild erectile dysfunction resulted in blood pressure changes similar to those observed after placebo administration. In patients with coronary artery disease (CAD), tadalafil administration before nitrate administration resulted in small decreases in blood pressure. The resulting mean maximal change in standing systolic blood pressure (SBP) after coadministration of sublingual nitroglycerin in patients with chronic stable angina was -36 mm Hg for tadalafil 5 mg, -31 mm Hg for tadalafil 10 mg, and -28 mm Hg for placebo. In addition, a larger number of men had a standing SBP <85 mm Hg after coadministration of sublingual nitroglycerin and tadalafil 5 mg (p <0.001 vs placebo) or tadalafil 10 mg (p <0.01 vs placebo) compared with coadministration with placebo. In patients with chronic stable angina taking doses of isosorbide mononitrate on a long-term basis, the mean maximal change in standing SBP was -23 mm Hg for placebo, -23 mm Hg for tadalafil 5 mg, and -26 mm Hg for tadalafil 10 mg. In a study of older subjects (>or=55 years of age) with no overt evidence of CAD, the resulting mean maximal change in standing SBP after coadministration of sublingual nitroglycerin was -25 mm Hg for tadalafil 10 mg, -29 mm Hg for sildenafil 50 mg, and -25 mm Hg for placebo. Cardiac mortality rates in tadalafil studies are consistent with the expected rate in this male population. Across all studies, the incidence rate of myocardial infarction was low in tadalafil-treated patients (0.43 per 100 patient-years) compared with patients who received placebo (0.6 per 100 patient-years), and the incidence rate was comparable to that observed in the age-standardized male population (0.60 per 100 patient-years). The incidence rate of presumed thrombotic strokes in tadalafil studies (0.27 per 100 patient-years) is comparable to the expected rate in this patient population. The data presented herein suggest that tadalafil can be safely used by healthy subjects and by patients with cardiovascular diseases. As with sildenafil, the use of tadalafil is contraindicated in patients receiving nitrate therapy because of the potential for significant hypotensive effects.