OBJECTIVES: To examine the prophylaxis use, incidence of VTE, major bleeding, minor bleeding and associated economic burden over 90 days in hospitalized medically-ill patients. METHODS: A retrospective study (January 01, 2005 to December 31, 2007) was conducted using a subset of the MarketScan Hospital Drug Database and its linked outpatient files from the Market Scan Commercial and Medicare Supplemental database. Eligible patients were selected if they were continuously enrolled in their health plan for at least 180 days prior to and 90 days following the index hospital discharge date, which is hospitalization with a medically ill diagnosis. Prophylaxis use is defined as the admission date of index hospitalization to 30 days after index hospital discharge and before the date of their first VTE events.  Patients’ demographics, healthcare visits and costs were compared using Chi-square testing and standardized differences. Risk-adjusted total healthcare costs between patients with events and without were estimated using the General Linear Model. RESULTS: In patients who were identified as medically ill (n=12,077), 6,464(53.52%) received anticoagulant therapy during their hospitalization and until 30 days after discharge. Compared with patients who did not receive any anticoagulant prophylaxis, patients who received anticoagulant prophylaxis had significantly lower VTE events (1.47% vs. 3.58%, p<0.0001). Although there was no significant difference in rates of major bleeding and minor bleeding, after risk-adjustment for pre-specified covariates, patients with outcome events were significantly associated with higher total healthcare costs (VTE: $40,523 vs. $17,698 p<0.0001; Major bleeding: $27,430 vs. $18,137 p<0.0001; Minor bleeding: $25,696 vs. $17,410 p<0.0001). CONCLUSIONS: Despite existing guidelines, few medically-ill patients are receiving anticoagulant prophylaxis. Appropriate anticoagulant prophylaxis use results in lower VTE event rates and total follow-up healthcare costs in hospitalized medically-ill patients.