Background: End-stage renal disease (ESRD) is a major clinical condition requiring renal replacement therapy. Hemodialysis (HD) and peritoneal dialysis (PD) are the two commonly used dialysis modalities, but they differ in the way they remove uremic toxins and excess fluid and may therefore have different efficacy and safety profiles. Objective: To compare the efficacy and safety of hemodialysis and peritoneal dialysis in the management of patients with ESRD. Methods: A hospital-based prospective observational study was conducted in the Department of Nephrology, King George Hospital, Visakhapatnam, over a period of six months from July to December 2024. Patients with ESRD receiving maintenance HD or PD were included. Demographic characteristics, vital signs, blood urea, blood urea nitrogen (BUN), serum creatinine, and dialysis-related complications were assessed before and after dialysis. Continuous variables were expressed as mean ± standard deviation, while categorical variables were expressed as percentages. Appropriate statistical tests were applied, with p<0.05 considered statistically significant. Results: Both HD and PD resulted in reductions in urea, BUN, and serum creatinine. The post-dialysis serum creatinine level was lower in patients receiving HD than in those receiving PD (3.1±1.2 vs. 4.2±1.3 mg/dL; p=0.02). Urea and BUN levels were also numerically lower following HD, although the between-group differences were not statistically significant. Vital signs remained broadly comparable between the two modalities. A significant difference was observed in the occurrence of peritonitis, which was higher among PD patients than HD patients (18% vs. 5%; p=0.002). Differences in sepsis and catheter-related infection were not statistically significant. Conclusion: Both HD and PD were effective in improving biochemical parameters in patients with ESRD. HD demonstrated greater reduction in serum creatinine and was associated with more rapid biochemical clearance, while PD provided a continuous dialysis approach with generally stable short-term vital signs. However, peritonitis was significantly more frequent with PD. The choice of dialysis modality should therefore be individualized based on the patient's clinical condition, infection risk, residual renal function, access to care, and preference.