The optimal medical regimen for the treatment of cocaine associated myocardial ischemia has not been defined. While animal and human data demonstrate the risks of beta-adrenergic blockade, studies in the cardiac catheterization laboratory suggest a beneficial role of nitroglycerin. We performed a prospective multicenter observational study to evaluate the clinical safety and efficacy of nitroglycerin in the treatment of cocaine associated chest pain at six municipal hospital centers. Of 246 patients presenting with cocaine associated chest pain, 83 patients were treated with nitroglycerin at the discretion of the treating physician. Relief of chest pain and/or adverse hemodynamic outcome were the primary endpoints. Baseline comparisons of patients treated with nitroglycerin to those not treated with nitroglycerin found that the treated patients were at higher risk of ischemic heart disease. They were older (36 years vs 32 years, p = 0.0008), more likely to have an ischemic electrocardiogram (27% vs 4%, p < 0.0001), to be admitted (94% vs 40%, p < 0.0001), and to have a discharge diagnosis of ischemic heart disease (41% vs 9%, p < 0.0001). Nitroglycerin was beneficial in 41 patients (49%; 95% CI, 38-60%): 37 patients (45%) had relief or reduction in the severity of chest pain and 4 patients (5%) had other beneficial effects. Only one patient had an adverse outcome (transient hypotension in the setting of a right ventricular infarct). Nitroglycerin is safe and possibly effective in the treatment of cocaine associated chest pain.