Metformin may reduce the risk of endometrial cancer whereas other drugs for the treatment of type 2 diabetes mellitus appear to increase it, although the evidence is still limited. We investigated this issue using data from a nested case–control study within the healthcare utilization databases of the Lombardy Region, Italy. This study included 376 diabetic women with endometrial cancer and 7485 diabetic controls matched for cases on age, date at cohort entry, and duration of follow-up. We used conditional logistic regression models to estimate the odds ratio (OR) of endometrial cancer in relation to use of antidiabetic drugs, adjusted for the Charlson’s comorbidity index, selected medical conditions, prescription of selected drugs, and concomitant use of other antidiabetic drugs. At cohort entry, no significant associations were observed for metformin [OR=0.99, 95% confidence interval (CI) 0.80–1.23], sulfonylureas (OR=1.14, 95% CI 0.91–1.42), insulin (OR=0.72, 95% CI 0.34–1.56), and other antidiabetic drugs (OR=1.21, 95% CI 0.75–1.95). When we considered use during follow-up, a borderline significant excess risk was found for metformin (OR=1.30, 95% CI 1.00–1.70). However, this estimate decreased to 1.07 (95% CI 0.82–1.41) when taking into account BMI using a Monte Carlo sensitivity analysis. No significant associations were found for sulfonylureas (OR=1.16, 95% CI 0.91–1.47), thiazolidinediones (OR=0.77, 95% CI 0.48–1.24), repaglinide (OR=1.32, 95% CI 0.94–1.87), incretins (OR=1.21, 95% CI 0.63–2.32), and insulin (OR=1.19, 95% CI 0.82–1.71). Our data indicate that metformin, insulin, and other antidiabetic drugs did not meaningfully affect the risk of endometrial cancer.