This study was carried out to investigate the effect of sildenafil (S) together with the influence of sodium nitroprusside (SNP) and acetylcholine (Ach) on isolated strips of rabbit corpus cavernosum. The in vitro effects of sildenafil on non-adrenergic, noncholinergic and nitric oxide (NO)-mediated cavernosal smooth muscle relaxation in diabetic rabbits, were also investigated. Diabetes mellitus was induced in adult male New Zealand white rabbits with alloxan (65 mg/kg, i.v). Cavernosal strips from agematched control and 5 months diabetic animals were mounted in organ baths containing Krebs-bicarbonate solution (pH 7.4, bubbled continueously with a gas mixture of 95% O2 plus 5% CO2, and maintained at 37oC. Isolated strips of control rabbit corpus cavernosum were stimulated isotonically with phenylephrine (10-5M) and relaxations were induced using increasing concentrations of Ach, SNP and S alone and in combination. Also, relaxation responses of control and diabetic strips precontracted with phenylephrine (10-5M) to electrical field stimulation (EFS, 4-20 Hz) or SNP (10-9 – 10-3M) were assessed in the absence and presence of a submaximal dose of sildenafil (10-6M). It was found that Ach, SNP and S relaxed the control rabbit corpus cavernosal strips in a dose-dependent manner. The relaxant effect of the test agents were ranked (from least inhibitory to most inhibitory) as follows: S, Ach plus S, SNP, SNP plus S, Ach. Moreover, it was observed that SNP-stimulated relaxations were significantly impaired in the corpus cavernosum from diabetic group compared to age-matched controls. Sildenafil (10-6M) significantly enhanced SNP-stimulated relaxation in control and diabetic groups. Electrical field stimulation-mediated relaxations of the corpus cavernosum were significantly impaired after 5 months diabetes mellitus and enhanced by sildenafil (10-6M). In conclusion, sildenafil enhances the relaxing effect of both SNP and Ach on the phenylephrine-induced contraction of rabbit cavernosal tissue. It could also be suggested that the impairment of NO-mediated relaxation of the diabetic corpus cavernosum reflect, at least in part, a defect in guanyl cyclase activity. These findings support the use of sildenafil as an effective, orally administered, treatment for diabetic erectile dysfunction.