Introduction <p>Patients with chronic kidney disease (CKD) have an increased risk of lower limbs fractures. During hospitalization for a fracture, these patients are also at higher risk of thrombotic events; therefore, prophylactic anticoagulation is often recommended. However, in advanced CKD the bleeding risk may outweigh the potential benefit of thrombosis prevention. The aim of our study was to evaluate whether enoxaparin prophylaxis compared with placebo influences the risk of major bleeding and thrombotic events in patients with advanced CKD hospitalized with lower limb fractures.</p> Methods <p>In a phase 2 randomized controlled trial, from March 2019 to October 2024, patients with lower limb fracture and advanced CKD were eligible. We randomly assigned 61 patients to the placebo (<i>N</i> = 30) and anticoagulation groups (enoxaparin 40&#xa0;mg; <i>N</i> = 31). Primary outcome was the risk of major bleeding. The main secondary objectives were risk of thrombosis, death, number of transfusions, dialysis requirement, hospitalization days, and the adverse events (AEs) related to anticoagulation.</p> Results <p>Both groups were similar, mean (SD) age of 65 (19) years; 54% were women, the eGFR of 24&#xa0;ml/min/1.73m². Hip fracture predominates (45.9%), followed by femur and tibia (31.1% and 23%, respectively). The primary outcome major bleeding occurred in 5 (16.1%) in the enoxaparin group and 4 (13.3%) in the placebo group. After adjusted analysis, comparing the enoxaparin with the placebo group, no increase in the risk of bleeding was observed (OR 1.28, CI 0.29–6.06, <i>p</i> = 0.741), nor was stratifying by CKD stages (p = &gt; 0.05). Thrombosis occurred in three (4.9%) patients: two (6.7%) in the placebo group and one (3.2%) in the enoxaparin group. Hospitalization days were fewer in the placebo group compared to the enoxaparin group (14 vs. 19, <i>p</i> = 0.023), reducing the hospital stay by 5 days (95% CI − 10.52 to − 0.09; <i>p</i> = 0.046). AEs attributed to the intervention, gastrointestinal bleeding occurred in 2 and 1 patient in the placebo and enoxaparin groups, respectively.</p> Conclusions <p>In patients with advanced CKD and lower limb fracture, prophylactic anticoagulation with enoxaparin, compared with no anticoagulation, did not promote more major bleeding. The incidence of DVT was very low in both groups; however, the study was not powered to evaluate differences in thrombosis risk, but associated with prolonged hospital stay, without clear evidence of an increased risk of major bleeding. These findings suggest that further studies are warranted to clarify the risk–benefit balance of anticoagulation in this population.</p> Trial registration <p>ClinicalTrials.gov, ID NCT06795698 Retrospectively registered 28/12/2024, IRB approval 257/18.</p>