Introduction Intensive care unit (ICU) patients with renal insufficiency are more likely to develop venous thromboembolism and are at an increased risk for bleeding. There is conflicting data on whether enoxaparin or unfractionated heparin (UFH) is preferred for preventing thromboembolism in this population. Therefore, the purpose of this study was to evaluate the safety of prophylactic enoxaparin versus UFH in ICU patients with renal impairment. Methods We conducted a single‐center, retrospective cohort study of ICU patients with renal impairment who received venous thromboembolism prophylaxis with either enoxaparin or UFH. Patients were included if they were at least 18 years of age, had renal impairment (acute kidney injury, severely decreased renal function, or end‐stage renal disease), and an ICU length of stay ≥72 h. The primary outcome was the proportion of patients experiencing a major bleeding event, including fatal bleed, symptomatic bleed in a critical area, or bleeding causing a ≥2 g/dl decrease in hemoglobin leading to a transfusion of ≥2 units of packed red blood cells. Results A total of 460 patients were included in the study. Of these, 231 received enoxaparin and 229 received UFH. In the unadjusted analysis, there was no difference in major bleeding events observed with enoxaparin compared to UFH (29.4% vs. 22.3%; p = 0.08) or rates of venous thromboembolism (4.3% vs. 3.5%; p = 0.64), respectively. After adjusting for confounding factors, enoxaparin showed a significant increase in major bleeding (OR: 1.84; 95% CI: 1.11 – 3.04; p = 0.02). Conclusion Thromboprophylaxis with enoxaparin in critically ill patients with renal impairment was associated with an increased risk of major bleeding compared to UFH.