Objective: There is a lack of cost effectiveness (CE) analyses of thromboprophylactic strategies (TSs) for total knee replacement (TKR) that incorporate outpatient care, long-term follow-up, or complications besides venothrombotic events (VTE: deep vein thrombosis, pulmonary embolism). The objective was to assess the CE of TSs for TKR from the health payer perspective including complications of VTE, hemorrhage, thrombocytopenia, and death. Methods: We searched national Veterans Affairs (VA) datasets for all health care use, outcomes and VA costs for patients receiving TKR within one year. Our follow-up was one year. Diagnostic codes were used to identify complications. Life-years gained (LYG) were calculated using actuarial tables. A comparative CE model, incorporating fondaparinux, was developed. Incremental cost-effectiveness ratios (ICERs) were calculated. Since no fondaparinux was used, we applied rates from published trials, and adjusted for the mean proportional increase in rates between 49 days (trial follow-up) and one year in Veterans. For fondaparinux, costs were estimated from mean costs of complications among the other TSs, with an adjustment for increased medication cost. One-way sensitivity analyses (SA) were performed by incorporating the mean probabilities of DVT among each other TSs into the least-costly TS or decreasing the costs of complication arms by one standard deviation. Results: There were 3037 patients, 131 VTEs, and 53 deaths. Dalteparin was dominant; the least-costly per patient with fewest VTEs ($16,310, 1.0%) compared to warfarin ($17,803, 3.5%), enoxaparin ($19,253, 2.4%), enoxaparin/warfarin ($23,641, 22.7%), and fondaparinux ($19,577, 1.6%). Thus, ICERS indicated more costs and more events with other TSs. Deaths occurred in 2% of dalteparin patients, thus ICERS for LYG (deaths) were warfarin $27,004 (1.7%), enoxaparin $33,232 (1.5%), enoxaparin/warfarin $40,479 (1.1%), and fondaparinux $20,355 (estimated 1.2%). Each SA showed dalteparin remained the least-costly TS per VTE avoided. Conclusion: Dalteparin was the least-costly TS and had the fewest VTEs.