BACKGROUND: Fondaparinux, a new synthetic pentasaccharide has proven to be a more potent thromboprophylactic drug compared to enoxaparin after major orthopaedic surgery. However, the safety of fondaparinux regarding wound healing has not yet been investigated. METHODS: We performed a single-centre prospective clinical trial, in which patients undergoing total knee arthroplasty or revision of at least one of the components of a previous knee arthroplasty were randomly assigned to thromboprophylaxis with fondaparinux or enoxaparin. The trial included 109 patients and wound discharge was compared. Secondary outcome measures were the amount of blood in the suction drain, postoperative transfusion rate, change in haemoglobin levels, haematocrit, intervention rate, time to regain flexion and rate of symptomatic thromboembolic events. RESULTS: 55 patients were treated with fondaparinux and 54 with enoxaparin. Base-line characteristics were similar. In both groups wound dressings remained dry after five (5.17+/-2.5 and 5.19+/-3) days postoperatively. There were no significant differences in any of our outcome measures. CONCLUSIONS: We did not find any significant difference in wound healing with fondaparinux after major knee surgery. Post hoc analyses suggested the study should have had a sample size of 155 in each group. We believe this trial should be used as a pilot study for further investigations concerning the safety of thromboprophylaxis.