OBJECTIVES: To compare healthcare expenditures following rapid-acting insulin analogues or human regular insulin utilization in a cohort of diabetic patients through the analysis of administrative databases. METHODS: A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. Propensity score matching was used to adjust for significant differences in the baseline characteristics between the two treatment groups. The direct cost was calculated as the sum of drug use, financial compensation by hospital DRG and outpatient activities (laboratory tests, services use and specialistic consultations), all regulated by government contracts. Generalised linear mixed models under gamma distribution were used to evaluate the costs. In case of cost variables with a large proportion of zeros, a two part model (logistic regression and glm with gamma distribution) was employed. RESULTS: After PS approach, 566 patients treated with human regular insulin were matched with an equal number of patients receiving rapid-acting insulin analogues. During the 3-year follow-up, the average number of hospitalizations was higher (0.54 vs. 0.47; P=0.028), and the average length of stay was 4,7 days longer (P <0.004), among patients receiving human regular insulin in comparison with those receiving rapid-acting insulin analogues. The annualized total healthcare costs were significantly lower in the rapid-acting insulin analogues group than human regular insulin group with an estimated difference between the two groups of 1336.7 € per patient per year (P=0.001) . CONCLUSIONS: This analysis from real-world clinical practice suggests that rapid-acting insulin analogue is associated with lower rates of hospitalizations and lower overall healthcare costs in diabetic patients.