Objective To analyze the predictive value of serum sterol regulatory element binding protein-1 (SREBP1), kidney injury molecule-1 (KIM-1), and zinc finger protein Zic family member 3 (ZIC3) levels for the occurrence of major adverse cardiac and cerebrovascular events (MACCE) in maintenance hemodialysis (MHD) patients.  Methods A total of 189 patients undergoing MHD in Handan First Hospital from May 2021 to May 2024 were prospectively enrolled as the MHD group, and a total of 189 healthy individuals from the health check-up department in the same period were recruited as the control group. Based on the presence or absence of MACCE, patients in the MHD group were further divided into MACCE group (n=51) and none MACCE (N-MACCE) group (n=138). Clinical data, serum levels of SREBP1, KIM-1 and ZIC3 were compared between MACCE and N-MACCE groups, and their correlations with MACCE were analyzed. Multivariate regression was conducted to explore the factors associated with MACCE. ROC curve and DCA curve were used to evaluate the predictive value and clinical practicability of serum levels of SREBP1, KIM-1 and ZIC3 for MACCE.  Results  The MHD group had higher serum levels of SREBP1 (t=13.937, P＜0.001) and KIM-1 (t=73.041, P＜0.001), and a lower level of ZIC3 (t=8.894, P＜0.001), as compared with those in the control group. The MACCE group had higher dialysis age (t=4.156, P＜0.001), triglyceride (t=2.802, P=0.006), blood calcium (t=3.644, P＜0.001), SREBP1 (t=5.812, P＜0.001), and KIM-1 levels (t=6.081, P＜0.001), and a lower ZIC3 level (t=5.764, P＜0.001), as compared with those in the N-MACCE group. Serum levels of SREBP1, KIM-1 and ZIC3 were significantly correlated with dialysis age (to SREBP1, r=0.435; to KIM-1, r=0.503; to ZIC3, r=-0.464; P＜0.001), triglyceride (to SREBP1, r=0.327; to KIM-1, r=0.352; to ZIC3, r=-0.381; P＜0.001) and blood calcium (to SREBP1, r=0.514; to KIM-1, r=0.487; to ZIC3, r=-0.497; P＜0.001). Dialysis age (OR=1.327, 95% CI: 1.080～1.630, P=0.007), blood calcium (OR=1.878, 95% CI: 1.189～2.965, P=0.007), SREBP1 (OR=2.539, 95% CI: 1.449～4.447, P=0.001), KIM-1 (OR=2.744, 95% CI: 1.454～5.178, P=0.002), and ZIC3 (OR=0.596, 95% CI: 0.432～0.822, P=0.002) were the associated factors for the occurrence of MACCE. The AUCs of serum SREBP1, KIM-1, ZIC3 and combination of the three serum levels for predicting MACCE were 0.783, 0.784, 0.774, and 0.900, respectively, indicating that combination of the three serum levels is better than SREBP1, KIM-1 or ZIC3 for predicting MACCE (Zcombination-SREBP1=2.601, P=0.009; Zcombination-KIM-1=2.533, P=0.011; Zcombination-ZIC3=2.857, P=0.004). When the high-risk threshold was set at 0.07～0.85, the prediction model of combined SREBP1, KIM-1 and ZIC3 levels had a better clinical practicability.  Conclusion Serum levels of SREBP1, KIM-1 and ZIC3 are abnormal in MHD patients with MACCE. Combination of the three serum levels has a higher value and clinical practicability for predicting MACCE.