Purpose. The effects of pioglitazone on sildenafil responsiveness in men with erectile dysfunction (ED) and a history of poor response to sildenafil were assessed. Methods. In a double-blinded study, 38 men aged 47 ± 1.5 years with moderate-tosevere ED and poor response to sildenafil were randomly assigned to take a premedication of pioglitazone 30 mg (n=19) or placebo (n=19) once daily for 9 weeks along with on-demand use of sildenafil during the last month of pioglitazonetreatment. Erectile function (EF) scores, assessed by EF domain of International Index of Erectile Function (IIEF), along with responses to Global Assessment Questions (GAQs) were major outcome measures. Serum levels of total testosterone (T), dehydroepiandrosterone sulfate (DHEAS), glucose, lipid profile and liver function test were minor outcome measures. Results.Pioglitazone significantly improved major outcome measures compared with placebo. The decrease from baseline of total cholesterol level was more in pioglitazonethan in placebo-treated groups. In 84% (32 out of 38) of the sildenafil poor-responders, at least one of the associated risk factors of ED was found. There was undiagnosed hypercholesterolemia in 34% of the subjects. Serum levels of T, DHEAS, glucose and other parameters remained unchanged in both groups. The intervention was well tolerated. Conclusions. Pioglitazone increased sildenafil response to improve ED of men with prior sildenafil failure and seems to be safe based on the present preliminary study. This improvement is likely regardless of fasting glucose and sex hormones levels.