Eleven patients with moderate to severe erectile dysfunction (ED) were given a single-dose corpus cavernosum injection of hMaxi-K, a "naked" DNA plasmid carrying the human cDNA encoding hSlo (for human slow-poke), the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel. Three patients each were given 500, 1000, and 5000 microg, and two patients were given 7500 microg, of hMaxi-K and monitored for 24 weeks. The primary objectives of this phase I study were safety and tolerability of escalating hMaxi-K doses as assessed by clinical evaluations and laboratory tests. Secondary efficacy objectives were measured primarily by use of the International Index of Erectile Function (IIEF) scale. Patient responses were validated by partner responses. There were no serious adverse events and no dose-related adverse events attributed to gene transfer for any patient at any dose or study visit. No clinically significant changes from baseline were seen in physical evaluations (general and genitourinary), hematology, chemistry, and hormone analyses, or in cardiac events evaluated by repeated electrocardiograms. Importantly, no plasmid was detected in the semen of patients at any time after the injections. Patients given the two highest doses of hMaxi-K had apparent sustained improvements in erectile function (EF) as indicated by improved IIEF-EF domain scores over the length of the study. One patient given 5000 microg and one given 7500 microg reported EF category improvements that were highly clinically significant and were also maintained through the 24 weeks of study. Efficacy conclusions cannot be drawn from results of a phase I trial with no control group. However, the promising primary safety outcomes of the study and preliminary indications of effectiveness provide evidence that hMaxi-K gene transfer is a viable approach to the treatment of ED and that further studies investigating the efficacy of hMaxi-K in patients with ED should be performed.