Venous thromboembolism (VTE) is a serious complication following orthopedic shoulder surgery; however, research is limited involving the break-even cost-effectiveness of VTE prophylaxis. The purpose of this study was to determine if the cost of aspirin and enoxaparin would break even for VTE prevention in patients following shoulder surgery. A drug retail database was used to obtain the lowest price for a course of aspirin (81 mg) and enoxaparin (40 mg) to perform a break-even cost analysis. Our institutional purchasing records were then searched to estimate the cost of treating a symptomatic VTE. The TriNetX national database was then queried to establish a rate of VTE after shoulder surgery. A break-even cost analysis was performed by determining the absolute risk reduction. This value was used to calculate the number of patients who are treated to prevent a single VTE while breaking even on cost. Sensitivity analyses were performed for drugs that did not break-even at the database derived VTE rates. A full medication course of aspirin and enoxaparin were found to cost $1.18 and $125.37, respectively. The cost of treating a symptomatic VTE was determined to be $9,407.00. Data from the TriNetX database showed rates of symptomatic VTE following shoulder arthroplasty, hemiarthroplasty, and arthroscopic rotator cuff repair were 1.60%, 1.50%, and 0.68%, respectively. Aspirin broke even on cost for all procedures if the initial rate decreased by an ARR of 0.01% (NNT=7,972). Similarly, enoxaparin broke even for shoulder arthroplasty and hemiarthroplasty if the initial rate of VTE decreased by an ARR of 1.33% (NNT=75). Enoxaparin did not break-even at the initial VTE rate for arthroscopic rotator cuff repair, however sensitivity analysis found enoxaparin was if the cost could be obtained for $60.00 or less. Enoxaparin broke even if the cost of treating a symptomatic VTE was $20,000.00 or higher. The cost of a three-week course of twice daily aspirin or once daily enoxaparin breaks even for VTE prophylaxis following shoulder arthroplasty and hemiarthroplasty if they reduce the VTE rate by a calculated absolute risk reduction. Given the lower rate of VTE observed for patients undergoing arthroscopic rotator cuff repair, only the three-week course of aspirin broke even under these conditions. Once-daily enoxaparin did not break-even at current market rate. Further research is needed to help determine optimal VTE prophylaxis after shoulder surgery.