Background: Patients with end-stage renal disease (ESRD) require specialized therapeutic interventions. The decreased renal function that modulates the physiology and presence of comorbidities is often associated with variations in the pharmacological response, thus increasing the risk of adverse drug events or reactions (ADE/ADRs) from co-administered drugs. Methods: A cross-sectional study to record comorbidities, drug–drug interactions (DDIs), ADE/ADRs in patients with chronic kidney disease of stage five in Greece. The study enrolled 60 patients of mean age 64.8 ± 12.9 years, undergoing hemodialysis three times a week. Demographic and social factors, comorbidities, laboratory test data, medication regimens, DDIs and the reporting of ADE/ADRs were analyzed. Results: Cardiovascular diseases and diabetes were the main comorbidities. In total, 50 different DDIs of various clinical significance were identified. CNS, GI-track, and musculoskeletal-system-related ADE/ADRs were most often reported by patients. ADE/ADRs as clinical outcome from DDIs were associated in 64% of the total identified DDIs. There was a positive trend between number of medications, ADE/ADRs report and DDIs. Conclusions: The impact of ADE/ADRs in ESRD patients should be always considered. Guidelines as well as continuous training in the context of evidence-based clinical practice by healthcare personnel on therapy administration and prevention of adverse events are important.