Previous studies established the efficacy of once-daily tadalafil for men with erectile dysfunction. However, no trial has focused on the effects of such treatment on men without previous experience using oral phosphodiesterase type 5 inhibitors. Patients were randomized (2:1) to once-daily tadalafil 5 mg (with possible down-titration to 2.5 mg; n = 146) or placebo (n = 69) for 12 weeks. Among 215 patients (mean age, 52 years), once-daily tadalafil treatment resulted in 61.7% of study participants reporting their ability to achieve and maintain erections as being much better or very much better (vs 21.7% on placebo; P < .001). Tadalafil significantly improved treatment satisfaction on the Erectile Dysfunction Inventory of Treatment Satisfaction (P < .001 vs placebo at end point) and psychosocial outcomes on the Self-Esteem and Relationship (SEAR) questionnaire (least squares mean difference in SEAR total score change from baseline, 11.8 [95% confidence interval, 5.4%-18.2%; P < .001 vs placebo]). Patients receiving once-daily tadalafil also experienced a higher proportion of daily self-reported spontaneous morning erections at end point (58.7%) compared with placebo (42.2%; P < .001 for the between-treatment difference in changes from baseline). However, no significant differences in parameters of endothelial dysfunction (including biomarkers and peripheral arterial tonometric measures) or nocturnal erections as recorded by the nocturnal electrobioimpedance volumetric assessment were observed between treatment groups. Tadalafil was well tolerated; adverse events included back pain, headache, and dyspepsia. These findings may contribute to a more comprehensive understanding of once-daily tadalafil's effects on phosphodiesterase type 5 inhibitor-naive men.