Hypoglycemia has been documented during regular hemodialysis (HD) in both diabetic and nondiabetic end-stage renal disease (ESRD) patients. The aim of this study was to evaluate the glycemic fluctuations in diabetic and nondiabetic ESRD patients during HD days using glucose-free and glucose-containing dialysate. We conducted a prospective interventional study in which 32 ESRD patients (16 diabetic and 16 nondiabetic) were included in the study. All the patients underwent two HD sessions with glucose-free bicarbonate solution (phase 1) and next two HD sessions done with 100 mg/dL glucose-containing dialysate (phase 2). Serum glucose was measured using a continuous glucose monitoring system at the 1st h, 2nd h, and 4th h in both the phases. Percentage of time above and below preset target range (70-140 mg/dL) in 24 h on HD days in both phases was noted. Glucose loss in effluent fluid from dialyzer also was estimated at the 1st h, 2nd h, and 4th h. Statistical analysis was performed using Statistical Package for the Social Sciences software. Data are expressed as mean ± standard deviation. The Chi-square test was used for comparison of categorical variables. Continuous variables were compared using Student's t-test. Value of P <0.05 was considered statistically significant. With glucose-free dialysate solution, 20 patients (diabetic - 15, nondiabetic - 5) had 22 episodes of hypoglycemia in 64 sessions and with glucose-containing solution, only five patients (diabetic - 4, nondiabetic - 1) had five episodes of hypoglycemia (P = 0.002). For all patients, glucose lost (g/h) in the effluent fluid was at lower values in phase 2 (5.91 ± 1.5) when compared to phase 1 (7.08 ± 10.9) (P <0.0002). This was also observed both among the diabetic and nondiabetic patients. The mean percentage of time below target out of 24 h on HD days in phase 1 was significantly higher as against phase 2 (33% vs. 18.7%; P = 0.0001) which was observed both among diabetic group (18.65% vs. 13.5%; P = 0.03) and nondiabetic group (48.12 % vs. 23.4%; P = 0.0003); the mean percentage of time above the target (>140 mg/dL) out of 24 h on HD days was significantly higher than phase 2 (21.1% vs. 9.3%; P = 0.0001). This was also observed among diabetics group of patients (18.8% vs. 8.6 %; P = 0.0001). Most of this time above target occurred during the post HD period. However, in the nondiabetic group, there was no significant difference between the two phases. Glucose-containing dialysate at 100 mg/dL significantly reduced the hypoglycemic episodes and also the intensity of hypoglycemia. Diabetic patients dialyzed with glucose-free dialysate had increased time above target (akin to Somogyi effect) in the post HD period compared to same patients dialyzed with glucose-containing dialysate. Hence, glucose-containing dialysate appears to offer better glycemic control and lesser glycemic fluctuations during HD days for both diabetic and nondiabetic ESRD patients.