Objective To compare the economic benefits of electronic system-based monitoring (ESM) and manual paper-based monitoring (MPM) in hand hygiene (HH) compliance, and provide reference for HH monitoring methods in high-risk clinical departments. Methods Eleven high-risk departments, including pulmonary and critical care medicine, department of trauma and micro-orthopedics, pediatric intensive care unit, department of infectious diseases, department of joint and sports medicine, general ward of pulmonary and critical care medicine, department of neurology, department of neurosurgery, department of radiochemotherapy for esophageal and mediastinal tumor lymphoma, department of radiochemotherapy for head, neck and children's tumor, and department of hematology in a large tertiary first-class hospital were analyzed. A decision tree model was constructed using TreeAge Pro 2022 software to calculate cost-effectiveness, cost-efficiency, Hawthorne effect, and indirect cost-benefit of the cost input and effect output during the implementation period of the two monitoring methods from December 2022 to May 2023. Results The total cost of the ESM method was lower than that of the MPM method (4 868.55 Yuan vs 7 122.12 Yuan), but HH compliance rate of the ESM method was lower than that of the MPM method (61.33% vs 78.79%). The cost-effectiveness ratio of MPM method was higher than that of ESM method (9 039.37 Yuan vs 7 938.28 Yuan), with an incremental cost-effectiveness ratio of 17.46%. The cost-efficiency ratio of MPM method was significantly higher than that of ESM method (72 013.35 Yuan vs 8 813.45 Yuan). The Hawthorne effect of MPM method was higher than that of ESM method (59.45% vs 47.90%). The cost-benefit ratio of MPM method was lower than that of ESM method (2 894.70 Yuan vs 4 765.98 Yuan). When the payment willingness was less than 18 500 Yuan, the ESM method was the better option for cost-effectiveness; When the input exceeded this threshold, the MPM method was the better option for cost-effectiveness. Conclusion For high-risk infection control departments, the ESM method is superior to MPM in cost-effectiveness, cost-efficiency and cost-benefit, but there is no statistically significant difference in the Hawthorne effect between the two methods.