Although intravenous morphine is commonly used for the treatment of chest pain in patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE ACS), its safety has not been evaluated. The CRUSADE Initiative is a nonrandomized, retrospective, observational registry enrolling patients with NSTE ACS to evaluate acute medications and interventions, inhospital outcomes, and discharge treatments. The study population comprised patients presenting with NSTE ACS at 443 hospitals across the United States from January 2001 through June 2003 (n = 57,039). Outcomes were evaluated in patients receiving morphine versus not and between patients treated with morphine versus intravenous nitroglycerin. A total of 17,003 patients (29.8%) received morphine within 24 hours of presentation. Patients treated with any morphine had a higher adjusted risk of death (odds ratio [OR] 1.48, 95% CI 1.33-1.64) than patients not treated with morphine. Relative to those receiving nitroglycerin, patients treated with morphine also had a higher adjusted likelihood of death (OR 1.50, 95% CI 1.26-1.78). Utilizing a propensity score matching method, the use of morphine was associated with increased inhospital mortality (OR 1.41, 95% CI 1.26-1.57). The increased risk of death in patients receiving morphine persisted across all measured subgroups. Use of morphine either alone or in combination with nitroglycerin for patients presenting with NSTE ACS was associated with higher mortality even after risk adjustment and matching on propensity score for treatment. This analysis raises concerns regarding the safety of using morphine in patients with NSTE ACS and emphasizes the need for a randomized trial.