Abstract: Erectile Dysfunction (ED) is a prevalent problem among most of diabetic patients. This defect is extensively treated by Sildenafil Citrate (SC), which is a potent phosphodiesterase -5 inhibitor (PDE-5 I). The mechanism of SC in treating ED in an experimental diabetic model, in conjunction with a potent antioxidant, vitamin E (vit E) is to be elucidated. Here, we report that, whether alone or in combination with E, SC induces penile erection, mostly, through organized modulation of blood neurotransmitters, namely, Serotonin (Ser), Dopamine (Dop), Nor-Epinephrine (NEP) and Nitric Oxide (NO), in addition to potassium (K), controlled calcium (Ca) influx modulation, affecting neurotransmitters release into the circulation, without apparent impact on sodium level (Na). In the present study, Ser, Dop, NEP and NO blood levels were together, significantly up-regulated in normo-glycemic and more significantly in alloxan diabetic rats by SC treatment, an effect which was non-significantly prohibited by E combination. K level was elevated by SC in normo-glycemic, but decreased in diabetic rats. This later action was reversed by E, however, Na level was only significantly elevated in diabetic group, given SC combined with E, but Ca levels were non-significantly changed. These actions of SC elucidate-in part-the mechanism of its action and necessitate care to its impact on diseases related to autonomic neurotransmission.