Introduction Erectile dysfunction (ED) is highly prevalent among men undergoing hemodialysis. Aim This study was performed to identify the influence of ED on the patient’s quality of life (QoL) and to evaluate the influence of depression on erectile function of these patients. Main Outcome Measures For this multicenter cross-sectional study, 275 patients were interviewed through questionnaires: the five-item version of the International Index of Erectile Function was used for diagnosing and classifying ED; the Medical Outcomes Study Questionnaire 36-Item Short Form Health Survey (SF-36) for scoring QoL; and the Hospital Anxiety and Depression Scale (HADS) to evaluate depressive symptoms. Linear regression was used to examine the associations between some of the variables and ED. Predialytic biochemical and hematological parameters were determined during the longer interdialytic period. Results Patients had a mean age of 48.6 ± 12.8 years, and the ED prevalence was 72.3%. Advanced age, diabetes and depression score were independent risk factors for the development of ED as confirmed by linear regression (P <0.001, P = 0.002, and P <0.001, respectively). QoL was worse among patients with any degree of ED, and the scores were statistically significant for overall health rating (P = 0.016), physical composite score (P = 0.003), bodily pain (P = 0.042), physical functioning (P <0.001), and vitality (P = 0.005). Furthermore, more severe forms of ED were associated with a lower QoL. After adjustment for some variables, such as age, time under dialysis, hemoglobin, albumin, parathyroid hormone, Kt/V, and depression, linear regression showed that domains related to poorer physical functioning (P = 0.047) and decreased vitality (P = 0.009) were significantly related to ED. Conclusion Depression is an important trigger for the development of ED in hemodialysis patients, and this sexual condition is an independent risk factor for their poor QoL.