Activation of endothelial cells and platelets is an initial step toward the development of cardiovascular disease. Erectile dysfunction (ED) may be an early manifestation of endotheliopathy. We evaluated the effects of tadalafil on cyclic nucleotides (cGMP and cAMP) and soluble adhesion molecules (E- and P-selectin [ES and PS]). The patients were divided into 2 groups on the basis of the presence (10 patients) or absence (9 patients) of cardiovascular risk factors (dyslipidemia, hypertension, and smoking). Nitric oxide (NO) was unmeasurable in all the patients. Tadalafil administration induced a significant increase in cGMP levels in both groups (P < .01). In contrast, cAMP significantly increased (P < .05) and PS decreased (P < .01) only in patients without cardiovascular risk factors. Tadalafil induced a beneficial effect on platelet activation in patients with ED without cardiovascular risk factors; this effect was not mediated by NO.