Background The immobilisation of the lower leg is associated with deep vein thrombosis (DVT). However, thromboprophylaxis in patients with a below-knee plaster cast remains controversial. We examined the efficacy and safety of nadroparin and fondaparinux to ascertain the need for thromboprophylaxis in these patients. Methods PROTECT was a randomised, controlled, single-blind, multicentre study that enrolled adults with an ankle or foot fracture who required immobilisation for a minimum of four weeks. The patients were randomly assigned (1:1:1) to a control group (no thromboprophylaxis) or to one of the intervention groups: daily subcutaneous self-injection of either nadroparin (2850 IE anti-Xa = 0.3 ml) or fondaparinux (2.5 mg = 0.5 ml). A venous duplex sonography was performed after the removal of the cast or earlier if thrombosis was suspected. The primary outcome was the relative risk of developing DVT in the control group compared with that in both intervention groups. This trial is registered at ClinicalTrials.gov, number NCT00881088. Results Between April 2009 and December 2015, 467 patients were enrolled and assigned to either the nadroparin group (n = 154), the fondaparinux group (n = 157), or the control group (n = 156). A total of 273 patients (92, 92, and 94 patients, respectively) were analysed. The incidence of DVT in the nadroparin group was 2/92 (2.2%) compared with 11/94 (11.7%) in the control group, with a relative risk of 5.4 (95% CI 1.2–23.6; p = 0.011). The incidence of DVT in the fondaparinux group was 1/92 (1.1%), yielding a relative risk of 10.8 (95% CI 1.4–80.7; p = 0.003) compared with that in the control group. No major complications occurred in any group. Conclusion Thromboprophylaxis with nadroparin or fondaparinux significantly reduces the risk of DVT in patients with an ankle or foot fracture who were treated in a below-knee cast without any major adverse events.