To identify the value and effectiveness of heparin-binding protein (HBP) in predicting acute abdomen complicated with sepsis as a diagnostic marker based on a comparative analysis of HBP, procalcitonin (PCT), C-reactive protein (CRP), white blood cell (WBC) count in patients with acute abdomen complicated with sepsis. Methods A retrospective analysis was performed on the clinical data of 88 patients who were admitted to the Emergency Department and Intensive Care Unit (ICU) of the South Division of the First Affiliated Hospital of USTC due to acute abdomen during September 2020 and September 2021. The patients were assigned to a control group (acute abdomen without sepsis, n=36), a group of acute abdomen complicated with sepsis (AAS group, n=36), and a group of acute abdomen complicated with septic shock (AASS group, n=16). HBP, PCT, CRP, and WBC levels were measured and compared using nonparametric methods; ROC curve analysis was utilized to assess the efficiency of these markers in the screening for sepsis; Spearman's correlation was employed to analyze the correlations of HBP with PCT, CRP, and WBC. Results Between the AAS group and the AASS group, there was significant difference in HBP, PCT, and CRP (P＜0.05) while there is no statistical significance in WBC (P＞0.05). In terms of predicting acute abdomen complicated with sepsis, HBP yielded an area under the ROC curve (AUC) of 0.941, larger than those of PCT, CRP, and WBC. With HBP as a diagnostic marker, the optimal cutoff value was 55.7 ng/mL, in which case the sensitivity was 0.972, and the specificity was 0.861. Conclusion HBP outperforms PCT, CRP, and WBC in the early diagnosis and clinical stratification of acute abdomen complicated with sepsis and appears to be a promising predictor of the condition in clinical application.