OBJECTIVES: To evaluate the safety and effectiveness of anticoagulants used for thromboprophylaxis in cancer patients. METHODS: A retrospective comparative effectiveness cohort study was conducted using data from the Medical Expenditure Panel Survey (MEPS). The incidence of venous thromboembolism (VTE), bleeding, and all-cause death events; and health-related quality of life (HRQoL) were used as the outcomes for the comparative effectiveness evaluation to evaluate the two comparative cohorts (prophylactic and matching-control). The effects of age, gender, race, and comorbidities on the clinical outcomes were controlled using logistic regression. RESULTS: The majority of the patients in the prophylactic cohort were on low-dose warfarin. The incidence of VTE was higher in the prophylactic cohort than in the matching-control (5.6% vs. 2.1%, respectively, with a relative risk (RR) of 2.66, 95%CI 2.64-2.68). There were more bleeding events (29% vs. 24%, RR 1.21, 95%CI 1.21-1.22) and all-cause death events (10.13% vs. 6.86%, RR 1.47, 95%CI 1.46-1.48) in the prophylactic cohort than in the matching-control cohort. However, after controlling for the effect of age, gender, race, and comorbidities these differences between the two cohorts became statistically insignificant. Lastly, the use of thromboprophylaxis was associated with a significant decline in physical quality of life, with no significant impact on mental quality of life. CONCLUSIONS: The present study findings support the current guidelines’ recommendation pertaining to VTE prophylaxis in cancer patients by providing evidence on the anticoagulants’ lack of effectiveness for thromboprophylaxis using data from real-world practice.