['To calculate and compare the direct medical costs of guideline-recommended prophylaxis with prophylaxis that does not fully adhere with guideline recommendations in a large, real-world population.', 'Discharge records were retrieved from the US Premier Perspective™ database (January 2003-December 2003) for patients aged≥40 years with a primary diagnosis of cancer, chronic heart failure, lung disease, or severe infectious disease who received some form of thromboprophylaxis. Univariate analysis and multivariate regression modeling were performed to compare direct medical costs between discharges who received appropriate prophylaxis (correct type, dose, and duration based on sixth edition American College of Chest Physicians [ACCP] recommendations) and partial prophylaxis (not in full accordance with ACCP recommendations). Market segmentation analysis was used to compare costs stratified by hospital and patient characteristics.', 'Of the 683 005 discharges included, 148,171 (21.7%) received appropriate prophylaxis and 534,834 (78.3%) received partial prophylaxis. The total direct unadjusted costs were $15,439 in the appropriate prophylaxis group and $17,763 in the partial prophylaxis group. After adjustment, mean adjusted total costs per discharge were lower for those receiving appropriate prophylaxis ($11,713; 95% confidence interval [CI], $11,675-$11,753) compared with partial prophylaxis ($13,369; 95% CI, $13,332-$13 406; P<0.01). Appropriate prophylaxis appeared to be associated with numerically lower unadjusted costs than partial prophylaxis, regardless of hospital size, rural/urban location, teaching status, and patient age and gender.'] Is appropriate VTE prophylaxis associated with lower direct medical costs?