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The cost, effectiveness, and safety of injectable anticoagulants used for thromboprophylaxis after orthopedic surgery were compared.This retrospective, observational, cross-sectional, cohort analysis of inpatient billing data was conducted from the institutional perspective. Patients who received dalteparin, enoxaparin, fondaparinux, or unfractionated heparin after orthopedic surgery were included in the analysis. The primary outcome measure was the mean aggregated cost per patient treated with each injectable anticoagulant. Secondary outcomes included the percentages of patients in each treatment group who had a venous thromboembolism (VTE) or major bleeding episode.Mean total adjusted costs were significantly lower for fondaparinux ($18,019) compared with other anticoagulants, with unfractionated heparin being the most costly ($20,835). Relative adjusted cost differences were 1.4% (p = 0.0127), 1.8% (p = 0.0105), and 14.6% (p < 0.0001) higher for enoxaparin, dalteparin, and unfractionated heparin, respectively, compared with fondaparinux. Significantly fewer fondaparinux-treated patients had a VTE event compared with the other treatment groups. The use of dalteparin was associated with fewer major bleeding events, and no significant differences in the rate of major bleeding events were observed among groups treated with fondaparinux, enoxaparin, or unfractionated heparin.A retrospective analysis of inpatient billing data showed that, among orthopedic surgery patients, fondaparinux was associated with lower institutional cost and a lower frequency of VTE than were dalteparin, enoxaparin, and unfractionated heparin. Dalteparin was associated with a lower rate of major bleeding events than was fondaparinux, but there were no significant differences in such events among fondaparinux, enoxaparin, and unfractionated heparin.