Background The benefits vs risk of pharmacological prophylaxis for thromboembolic disease in orthopedic patients remain controversial. Pharmacological thromboprophylaxis regimes are commonly used in this patient group. Few studies specifically examine wound complications attributable to this therapy. In this prospective trial, we investigated the effect of various regimens on postoperative wounds. Methods A prospective, observational, multicenter study involving patients undergoing elective hip or knee arthroplasty was undertaken. Patients were divided into 3 groups depending on thromboprophylaxis: no anticoagulation, aspirin, or low molecular weight heparin (LMWH) (enoxaparin). Surgical wounds were evaluated for each regime using the Southampton Wound Assessment Score. Results Over a 12-month period, 327 patients were enrolled with a mean age of 68.1 years (±11.2 years). There were 105 patients in the no anticoagulation group (32.1%), 97 patients in the aspirin group (29.7%), and 125 patients in the LMWH group (38.2%). Wound scores were evaluated for evidence and amount of discharge. The use of LMWH conferred a 4.92 times greater risk and aspirin a 3.64 times greater risk of wound discharge than no pharmacological thromboprophylaxis (P <.0001). There were no significant differences in the incidence of deep vein thrombosis or pulmonary embolus between groups either as an inpatient or postdischarge. Conclusion There is a significant increase in the risk of wound discharge when aspirin or LMWH is used in arthroplasty patients. As potential complications of wound problems are significant, a more balanced view of risk vs benefit needs to be taken when prescribing thromboprophylaxis for this patient group.