Objective To evaluate the effects of glucose-containing dialysate versus glucose-free dialysate on blood pressure variability and blood glucose variability in maintenance hemodialysis (MHD) patients and to assess safety. Methods MHD patients from 12 hospitals were enrolled between October 2024 and June 2025. According to the randomized block design, patients were randomly divided into the glucose-containing dialysate group (experimental group) and the glucose-free dialysate group (control group). During hemodialysis sessions, blood pressure were monitored at 0, 1, 2, 3, and 4 hours, and blood glucose was measured at 0, 2, and 4 hours monthly for six consecutive months. Hypotension episodes and hypoglycemic episodes were recorded throughout dialysis. Results A total of 244 MHD patients were included, with 122 in each group. Compared with the control group, the experimental group showed significantly lower systolic blood pressure variability [dialysis for 2 hours: 9.92 (7.92, 12.52) vs. 11.95 (9.45, 15.36) mm Hg (1 mm Hg=0.133 kPa), P<0.001; during the 0-2 hour dialysis period: 2.60 (1.24, 3.97) vs. 3.74 (2.03, 6.52) mm Hg, P=0.011], diastolic blood pressure variability [during the 0-4 hour dialysis period: 3.85 (1.49, 6.69) vs. 4.72 (1.99, 8.46) mm Hg, P<0.001], blood glucose variability [dialysis for 2 hours: 0.16 (0.12, 0.20) vs. 0.18 (0.13, 0.23) mmol/L, P=0.002; dialysis for 4 hours: 0.17 (0.13, 0.22) vs. 0.21 (0.17, 0.26) mmol/L, P<0.001; during the 2-4 hour dialysis period: 0.04 (0.02, 0.08) vs. 0.07 (0.03, 0.10) mmol/L, P=0.004], incidence rates of hypotension (32.9% vs. 33.3%, P=0.005) and incidence rates of hypoglycemia (0.42% vs. 4.02%, P<0.001). Conclusions Glucose-containing dialysate reduces both blood pressure variability and blood glucose variability more effectively than glucose-free dialysate during hemodialysis. Compared with glucose-free dialysate, the glucose-containing dialysate demonstrated a lower incidence of hypotension episodes and hypoglycemic episodes.