Summary. Background: Diabetes mellitus is generally not recognized as an important risk factor for venous thromboembolism (VTE). However, clinical observations and case reports have suggested that patients with diabetes and hyperosmolarity may be at increased risk for VTE. Objectives: To determine the risk of VTE in patients hospitalized for diabetes with hyperosmolar state compared to patients with other acute medical illnesses. Patients/methods: The California Patient Discharge Data Set was used to determine the incidence of first-time VTE in all patients admitted between 1995 and 2000 for diabetes with hyperosmolarity and 11 other acute medical conditions. Proportional hazard modeling was used to adjust for age, race, gender, and prior hospitalization within 3 months. Results: Among 2859 patients with diabetes and hyperosmolarity, 34 (1.2%) developed VTE during the hospitalization and 14 (0.5%) developed VTE within 91 days after discharge. In an adjusted multivariate model comparing the risk of VTE to cases with depression, patients with hyperosmolarity had a significantly higher risk of VTE [hazard ratio (HR) = 16.3; 95% confidence interval (CI): 10-25] comparable to the risk associated with sepsis (HR = 19.3; 95% CI: 13-29) or acute connective tissue disease (HR = 21; 95% CI: 15-31). Compared to uncomplicated diabetes, patients with hyperosmolarity had a significantly higher risk of VTE (HR = 3.0; 95% CI: 2.1-4.5) whereas patients with ketoacidosis were not at higher risk (HR = 1.2; 95% CI: 0.8-1.7). Conclusions: Patients hospitalized for diabetes with hyperosmolarity are at increased risk for developing VTE both during their inpatient stay and in the 3 months after discharge. Thromboprophylaxis in these patients appears warranted, and extended prophylaxis for after hospital discharge should be studied.