Abstract. Introduction: To the authors' knowledge, treatment of patients with cocaine-associated acute coronary syndromes has not been rigorously investigated in symptomatic patients. Objective: To perform a randomized double-blind trial of diazepam, nitroglycerin, or both for treatment of patients with potential cocaine-associated acute coronary syndromes. Methods: Patients with potential cocaine-associated acute coronary syndromes were randomized to treatment with either diazepam, nitroglycerin, or both every 5 minutes or until symptom resolution. Outcomes were chest pain resolution (measured by visual analog scale), and changes in blood pressure, pulse rate, cardiac output (L/min), cardiac index (L/min/m2), stroke volume (mL/beat), and stroke index (mL/beat/m2) over the 15-minute treatment period. To adjust for seven outcomes using the Bonferroni correction, alpha was set at 0.007. Results: Forty patients were enrolled (diazepam, 12; nitroglycerin, 13; both, 15). Patients had a mean age (±SD) of 35.4 (±7.5) years; 75% were male. They presented a mean of 5 hours and 37 minutes after cocaine use. Baseline demographics, cocaine use patterns, chest pain characteristics, and initial electrocardiograms were similar for all groups. Chest pain severity improved similarly in the threev groups [-33.3 mm (±8.0); -30.7 mm (±7.1); -33.0 mm (±7.9); p = 0.6]. The stroke index decreased during the 15-minute treatment period for all groups (diazepam, -8.7 (±3.3); nitroglycerin, -3.1 ± 2.8; both, -1.8 (±3.1) mL/beat/m2; p = 0.03). After adjustment for differences between baseline hemodynamic and cardiac profiles and multiple comparisons, there was no difference in any response to therapy over time for the different treatments. Conclusions: For treatment of patients with potential cocaine-associated acute coronary syndromes, chest pain resolutions and changes in cardiac performance are not different in patients treated with diazepam or nitroglycerin. In this study, the use of both agents did not offer any advantage over either agent alone.