OBJECTIVES: To evaluate the impact of risk factors on the development of stress-related upper gastrointestinal bleeding in severe head injury patients randomized to treatment with a 6.25 mg/hr continuous ranitidine infusion or placebo. DESIGN: Prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Ten intensive care units in the United States. PATIENTS: Patients with severe head injury, defined as having a Glasgow Coma Score of < or = 10, were eligible for enrollment. INTERVENTIONS: Ranitidine 6.25 mg/hr or saline placebo was administered by continuous infusion for a maximum of 5 days. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated every 8 hrs for the presence of stress-related upper gastrointestinal bleeding. Bleeding developed in 15 (19%) of 81 placebo-treated patients vs. three (3%) of 86 ranitidine-treated patients (p = .002). None of the individual risk factors had a significant effect on bleeding frequency. No bleeding occurred in the four patients with one risk factor. Placebo bleeding rates in patients with 2, 3 to 5, and > 5 risk factors were 20%, 20%, and 18%, respectively. For the ranitidine-treated patients, bleeding was reported in 0%, 5%, and 0% in the 2, 3 to 5, and > 5 risk factor subgroups, respectively. Pneumonia occurred in 19% of the placebo-treated patients vs. 14% in the ranitidine treatment group. CONCLUSIONS: The full risk to develop stress-related upper gastrointestinal bleeding was realized when two risk factors were present concomitantly. The presence of additional risk factors did not increase the occurrence of bleeding. A continuous infusion of ranitidine at 6.25 mg/hr provided significant protection from bleeding, regardless of the number of risk factors present.