Purpose We assessed changes in quality of life after 6 months of self-injections of prostaglandin E1 for the treatment of erectile dysfunction. Materials and Methods A prospective study was done at a university affiliated Veterans Affairs medical center of patients using prostaglandin E1 at home. Quality of life was assessed with the Case Western Reserve University sexual functioning questionnaire and the Duke health profile. These questionnaires were administered before initiation and after 6 months of prostaglandin E1 therapy. Results Of 16 subjects injecting prostaglandin E1 at home 15 completed 6 months of therapy, and 13 of them completed both questionnaires. While using prostaglandin E1 we found an increase in the frequency of sexual activity from 2.9 to 5.5 times during the prior month (p = 0.01), rigidity of erection scores from 3.8 to 7.6 (p = 0.002, score 0--no erection to 8--full erection) and sexual satisfaction scores from 2.5 to 4.1 (p = 0.03, score 0--extremely unsatisfied to 5--extremely satisfied). We also found improvements in mental health scores from 80.0 to 92.3 (p = 0.007), social health scores from 61.5 to 80.8 (p = 0.004) and self-esteem scores from 72.3 to 86.9 (p = 0.01) on a scale of 0 to 100, where a higher score indicates better health. Conclusions Self-injection of prostaglandin E1 improves sexual satisfaction and quality of life in men with erectile dysfunction.