Continuous neuraxial or deep peripheral nerve blockade used to provide postoperative analgesia after major orthopaedic surgery is associated with a risk of spinal or perineural haematoma, especially in patients concomitantly receiving anticoagulants. Limited data on the use of fondaparinux in surgical patients in whom this procedure is performed are available. The EXPERT trial was an observational international study in patients undergoing major orthopaedic surgery designed to evaluate the overall efficacy and safety of once-daily 2.5 mg fondaparinux initiated 6 to 12 hours post-operatively and administered for 4±1 weeks after surgery. A 48-hour “therapeutic window” was applied in patients in whom a neuraxial/deep peripheral indwelling catheter was placed: one of the planned doses of fondaparinux was omitted, the catheter was removed 36 hours after the previous fondaparinux dose, and the next fondaparinux dose administered 12 hours after catheter removal. The primary endpoints were symptomatic venous thromboembolism (VTE) and major bleeding 5±1 weeks after surgery. These events were validated by an independent adjudication committee. Overall, 5704 patients (mean age ± SD: 66 ± 12 years) were recruited between July 2003 and October 2004. They underwent surgery for total hip replacement (52%, n=2941), knee replacement (40%, n=2263), hip fracture (6%, n=353), or other indications (3%, n=148). Fondaparinux was given for a median of 35 (range: 1–105) days. Many operations (62%) were performed under regional anaesthesia only. A neuraxial or deep peripheral nerve block catheter was placed in 29% (n=1630) of patients. It was removed between one and two days after surgery in 43% (706/1626), and between three and six days after surgery in 57% (920/1626). Overall, the rate of symptomatic VTE was 1.0% (54/5387); it was 0.8% (13/1535) in patients with catheter and 1.1% (41/3852) in patients without catheter, giving an odds ratio of 0.79 (95% CI: 0.42 to 1.49) in favour of patients with a catheter. The upper limit of the 95% CI being below the predetermined non-inferiority margin of 1.75, the efficacy of fondaparinux in patients with a catheter was therefore not inferior to that observed in patients without a catheter. The rate of major bleeding was 0.8% (42/5382) overall, 0.5% (7/1532) in patients with catheter and 0.9% (35/3850) in patients without catheter. No spinal or perineural hematomas or nerve damage were reported. At 5±1 weeks, 23 (0.4%) patients had died. In conclusion, 2.5 mg fondaparinux given daily for 4±1 weeks after major orthopaedic surgery was both effective and safe in routine practice. This benefit-risk ratio was similar in 1630 patients with a neuraxial/ deep peripheral indwelling catheter in whom a 48-hour “therapeutic window” was applied.