The objective of this study was to examine venous thromboembolism (VTE) prophylaxis use, risk reduction, and readmission in medically ill patients during hospitalization and after discharge. This 5-year retrospective study linked outpatient files from MarketScan Commercial and Medicare Supplemental databases. Patients were categorized into prophylaxis and non-prophylaxis groups based on guideline-recommended anticoagulant use from the index date to 180 days posthospital discharge and before the first VTE event date. Outcome variables were VTE events and rehospitalization. Risk adjustment was conducted within the prophylaxis group and between the prophylaxis and non-prophylaxis groups using propensity score matching. Among 4467 patients, 28.99% of the patients (n = 1295) were admitted with cancer, 18.03% (n = 805) with pneumonia, 14.06% (n = 628) with heart failure, 11.06% (n = 494) with stroke, 11.11% (n = 496) with sepsis, 8.08% (n = 361) with infectious diseases, 5.6% (n = 250) with severe respiratory disorders, 1.81% (n = 81) with inflammatory bowel disease, 1.05% (n = 47) with obesity, 0.20% (n = 9) with neurologic disorders, and 0.02% (n = 1) with acute rheumatic fever. Among those with 180-day continuous enrollment after the index date (n = 3511), 51.81% (n = 1819) received anticoagulant therapy only, 2.48% (n = 87) received mechanical compression treatment only (stocking or pneumatic compression), and 4.41% (n = 155) received both during hospitalization. Anticoagulant therapy rates ranged from 88.64% (obesity) to 32.39% (inflammatory bowel disease). Among anticoagulant therapy patients, 740 patients (40.68%) received low-molecular weight heparin only and 806 patients (44.31%) received unfractionated heparin. After risk adjustment, compared with patients without VTE prophylaxis, anticoagulant prophylaxis patients had lower VTE (3.62% vs. 4.27%, P < 0.04) and readmission rates (24.22% vs. 27.95%, P < 0.02) during the 6 months post-index hospital admission. In conclusion anticoagulant prophylaxis is underutilized and is associated with reduced VTE risk and a decrease in rehospitalizations for medically ill patients.