Objective To explore the risk factors and prevention strategies of blood glucose fluctuation during hemodialysis (HD) in patients with diabetes mellitus (DM). Methods Retrospective analysis of the clinical data of 86 T2DM patients with concurrent pattern HD and DM admitted to Huainan Oriental Hospital Group General Hospital from August 2020 to February 2022, set as a training set; According to whether blood glucose fluctuated during HD, the patients were divided into blood glucose fluctuation group (44 cases) and no blood glucose fluctuation group (42 cases). According to the same criteria, 29 T2DM patients with DM parallel regular HD from March to August 2022 were selected as the validation set for external validation. After LASSO regression analysis, multivariate Logistic regression analysis was performed, and establish nomogram prediction model, and the model was evaluated. Results During HD, the blood glucose fluctuation range of patients was 1.62~27.81 mmol/L, with an average of (8.46±3.25) mmol/L. With the progress of dialysis, the blood glucose decreased the most in 1 hour of hemodialysis; After 2 hours of hemodialysis, the blood sugar increased slightly, but the change in blood sugar was generally flat. During HD, 19 patients (30 times) had hypoglycemia (22.09%), and 25 patients (47 times) had hyperglycemia (29.07%). Four predictors were screened by LASSO regression analysis, and multivariate Logistic regression analysis showed that DM duration≥18.2 years, poor self-care ability, systolic blood pressure (SBP)≥152.3 mmHg, glycated hemoglobin glycosylated hemoglobin (HbAlc)≥8.4% are independent risk factors for blood glucose fluctuations during HD (P<0.05). The evaluation results show that the nomogram prediction model has good discrimination, high accuracy and good effectiveness. Conclusion Duration of DM≥18.2 years, poor self-care ability, SBP≥152.3 mmHg, HbAlc≥8.4% were independent risk factors for blood glucose fluctuations during HD. In clinical treatment, it is necessary to pay close attention to the changes of various indicators in the process of HD in patients with DM to clarify the risk of blood sugar fluctuations, so as to adjust the treatment plan more accurately and in a timely manner