OBJECTIVES: To test the efficacy of a sildenafil (50 mg) and apomorphine (3 mg) sublingual combination in treating male Erectile Dysfunction (ED) in comparison to sublingual sildenafil (50 mg) that shows an increasing number of non-responders. METHODS: In all, 50 eligible ED patients were enrolled into a prospective single-blinded crossover study with two treatment periods, each of 4 weeks, separated by a 2-week washout period. A randomization list in blocks in closed packets was used to randomize the patients to receive sildenafil then the combination or the combination then sildenafil. The primary efficacy endpoint was the percent of attempts resulting in erection firm enough for intercourse. Other efficacy endpoints included the percent of attempts resulting in successful intercourse, change in the score of the 5-item version of the International Index of Erectile Function (IIEF-5) from baseline, response to Sexual Encounter Profile (SEP) diary questions 2 and 3, and patient’s preference (Of the two study interventions, which one did you prefer?). RESULTS: Only 43 patients completed the whole schedule and had results evaluable for efficacy. Sildenafil - apomorphine combination had a significantly higher estimate than sildenafil in regard to the mean percent of attempts resulting in erection firm enough for intercourse (77.6% vs. 63.1%, p <0.001) and resulting in successful intercourse (51.1% vs. 34%, p <0.001), as well as erectile function as evaluated by the change in the median IIEF-5 score from baseline (18 vs. 15 with baseline of 7, P<0.001). Also, the proportion of affirmative answers regarding the SEP diary was significantly higher after the combination (question 2: 79.1% vs. 55.8% P<0.01 and question 3: 65.1% vs. 44.2%, P<0.05). At the end of the study, patient preference was 88.4% for the combination and 4.6% for sildenafil. CONCLUSIONS: Sildenafil - apomorphine sublingual combination was significantly more effective than sublingual sildenafil in treating ED.