Introduction: Bleeding in critically ill patients may lead to potentially serious consequences. We evaluated the association between major bleeding events and clinical outcomes in patients receiving either dalteparin or unfractionated heparin for thromboprophylaxis. Hypothesis: We hypothesized that major bleeding in critically ill patients is associated with prolonged length of stay, increased use of blood products, and increased risk of ICU and hospital mortality. Methods: In the PROTECT trial, major bleeding was adjudicated by 2 independent blinded investigators and defined as life-threatening, occurring into critical sites, requiring? 2 units of red blood cells or an invasive intervention, or associated with a decrease in systolic blood pressure of? 20 mmHg or an increase in heart rate of? 20 beats/minute in the absence of other causes. We used multivariable Cox proportional hazards regression analysis with adjustment of age, APACHE II score, and use of inotropes, vasopressors and mechanical ventilation at study enrolment to asses the association between major bleeding, use of blood products and mortality. Results: Among 3746 patients, 208 (5.6%) had major bleeding. The median duration of major bleeding was 2 (25th-75th:1-4) days. Patients with major bleeding had a significantly longer median duration of mechanical ventilation (17 vs 5 days, p<0.001), ICU (23 vs 9 days, p<0.001) and hospital stay (36 vs 21 days, p<0.001). More patients with major bleeding were transfused platelets (25.0%vs 1.7%, hazard ratio [HR] 18.61, 11.71-29.57), red blood cells (92.8% vs.29.4%, HR 8.54, 6.70-10.89), and plasma (43.8% vs. 5.4%, HR 15.81, 11.27-22.18) compared to those who did not. Patients with major bleeding had also a significantly higher ICU (39.4% vs. 14.3%, HR 1.64, 1.27-2.10) and hospital mortality (51.0% vs. 21.7%, HR 2.09, 1.69-2.57). Conclusions: In critically ill medical-surgical patients, major bleeding was associated with a higher rate of transfusion of blood products, prolonged mechanical ventilation and longer ICU and hospital stays. Furthermore, major bleeding was independently associated with an increased risk of death.