Objective: We studied whether long-term use of 5 mg tadalafil once daily improved baseline erectile function or prevented erectile dysfunction (ED) in men with diabetes. Design and Method: Men with ED and diabetes were assigned to 20 mg tadalafil on-demand or 5 mg tadalafil once daily. When men completed the questionnaire after 2 years of treatment, they also stopped the medication for 4 weeks to check baseline erectile function. The primary efficacy variable was the IIEF-EF score. Secondary variables included a change in the scores IIEF Q3 and Q4 from baseline, changes in all domain scores on the IIEF from baseline, SEP2 and SEP3, and GAQ. Rigiscan® measurements of nocturnal penile tumescence and rigidity (NPTR) were also carried out after the 2year treatment. Results: The study enrolled 118 men. After 2 years, daily treatment group had a greater change in IIEF-EF score from baseline (7.3 vs. 2.4, P < 0.0001). The changes in IIEF from baseline on Q3 (1.4 vs. 0.4, P < 0.0001) and Q4 (1.4 vs. 0.3, P < 0.0001) were higher in the daily group. Differences between daily and on-demand groups were significant for SEP2 (53.8% vs. 32.3%) and SEP3 (56.6% vs. 15.4%). Normal EF domain scores at the end of study were achieved by 20.7% in daily groups. Normal NPTR at tend of study was achieved by 13.2% only in the daily group. Conclusions: Long-term use of 5 mg tadalafil once daily was more beneficial for improving baseline erectile function or preventing ED than the on-demand pattern in men with ED and diabetes.