OBJECTIVES: Intracavernosal injection with a combination of agents (ie, phentolamine plus papaverine or alprostadil) has been used in an effort to increase efficacy and reduce side effects compared with single agents. The purpose of this pilot study was to determine the potential role of oral alpha-blockers in combination with intracavernosal therapy in men with erectile dysfunction, for whom intracavernosal therapy alone failed. METHODS: Thirty-eight consecutive men with moderate to severe erectile dysfunction on the basis of history and examination and with minimal or no therapeutic response to intracavernosal alprostadil injection therapy were evaluated. All patients received daily doxazosin titrated to 4 mg over 3 weeks in combination with intracavernosal therapy as needed for 12 weeks. Efficacy was assessed at 4, 8, and 12 weeks after doxazosin titration using the 1 5-item, self-administered International Index of Erectile Function (IIEF) and a global efficacy question (GEQ: Did treatment improve your erections?). RESULTS: For the group, the mean baseline IIEF score before therapy was 29.7+/-9.8. After intracavernosal therapy (mean dose 34.7+/-7.3 microg), IIEF improved to 36.1+/-1 1.4 (17.7%). After addition of doxazosin, IIEF improved to 48.6+/-13.4, 46.4+/-10.9, and 51.5+/-14.3 at 4, 8, and 12 weeks, respectively (P < 0.01). The GEQ response improved from 25.7% at baseline to 81.4% at 12 weeks. Overall 22 (57.9%) of 38 patients with the combined regimen had a significant (more than 60% improvement in IIEF) therapeutic response. CONCLUSIONS: The addition of an oral alpha-blocker may have a beneficial effect in patients with erectile dysfunction for whom intracavernosal therapy alone fails. The synergistic effects of vascular dilation and blockade of sympathetic inhibition may explain this response. The potential role of alpha-blockade in synergy with other agents designed to treat erectile dysfunction remains to be determined.