In this study, we aimed to determine the hemodynamic mechanisms through which cigarette smoking, as an independent risk factor, induces erectile dysfunction (ED). We performed a standard ED evaluation that included history; a physical exam; and serum glucose, testosterone, and prolactin levels. We then excluded ED patients with abnormal androgen profiles and patients with ED risk factors other than smoking. A total of 109 ED patients entered the study, including 71 current smokers and 38 nonsmokers. All patients then underwent extensive evaluation, including nocturnal penile tumescence and rigidity (NPTR) monitoring with Rigiscan, followed by pharmacopenile duplex ultrasonography (PPDU) and redosing pharmacocavernosometry (RPC). Results of the above tests were compared in the smoker and nonsmoker groups. We also performed receiver operating characteristic (ROC) curve analysis to determine which diagnostic parameter is most affected by cigarette smoking. The 4 most significant variates served as input features for a logistic regression model, designed to predict smoking. The average age for smokers and nonsmokers was 44.3 and 51.2 years, respectively (P = .02). Eighty-six percent of smokers had abnormal NPTR testing compared with 55% of nonsmokers (P = .02). The average peak systolic velocity (PSV) was 26.8 and 31.2 cm/s for smokers and nonsmokers, respectively, and this difference was not found to be statistically significant (P = .19) in this study. On performing RPC, an abnormal maintenance flow (MF) of >5 mL/min was detected in 89% of smokers and in 47% of nonsmokers, and the difference was significant (P < .01). With the use of smoking as the outcome, the ROC area of different diagnostic parameters was as follows: 0.79 for penile base rigidity, 0.58 for PSV, and 0.77 for MF. A logistic regression model that used the 4 most significant variates as input features yielded a ROC of 0.857. The results of NPTR testing in our smoker and nonsmoker groups indicated that ED in smokers is mainly of organic etiology. On the basis of the PPDU findings and the higher incidence of abnormal MF in the smoker group and its relatively high ROC value, we concluded that dysfunction of penile veno-occlusive mechanisms plays a substantial role in the development of ED in smokers.