AIM: To investigate the interactive effects of blood glucose and blood calcium on the prognostic impact of patients with acute severe pancreatitis (SAP) and to analyze their predictive efficacy on prognosis. METHODS: One hundred and seven patients with SAP admitted to our hospital from September 2019 to October 2022 were selected for the study and were divided into poor and good groups according to their prognosis within 28 d. The blood glucose, blood calcium, modified Marshall score, bedside acute pancreatitis severity score  (BISAP) were compared between the two groups before treatment, after 3 d of treatment, and after 7 d of treatment, and the correlation between blood glucose, blood calcium and modified Marshall score and BISAP score was analyzed. The blood glucose levels of patients with different blood calcium were compared. Cox regression was used to analyze the factors associated with prognosis. The presence and type of interaction between blood glucose and blood calcium on prognosis were analyzed using the interaction coefficient γ and relative risk (RR) values. The subject operating characteristic curve (ROC) was used to analyze the predictive efficacy of blood glucose and blood calcium on prognosis. RESULTS: The blood glucose, modified Marshall score, and BISAP score of the adverse group after treatment were higher than those of the good group, while the blood calcium was lower than that of the good group (P<0.05). After 3 and 7 days of treatment, blood glucose was positively correlated with improved Marshall score and BISAP score (P<0.05). The blood glucose level in patients with decreased blood calcium was higher than that in patients with normal blood calcium (P<0.05). The decrease of blood calcium had positive interaction with the increase of blood glucose (P<0.05). After 3 and 7 days of treatment, the AUC of blood glucose combined with blood calcium was greater than that predicted by single index (P<0.05). CONCLUSION: Blood glucose and blood calcium are related to the severity of the disease in SAP patients. There is an interaction between blood glucose and blood calcium in predicting the prognosis of SAP patients. The combined detection of blood glucose and blood calcium has a certain predictive effect on the prognosis of SAP patients.