Background: We characterized stroke mechanisms and risk factors in a cohort of cocaine users across a broad range of socioeconomic status to inform stroke management and prevention efforts. Methods: Cases were consecutive patients ≥ 18 years with acute ischemic stroke (AIS) and enrolled into a prospective registry, with history or laboratory confirmed cocaine use. Non-cocaine user AIS controls matched for age, sex, and race were derived from the same study population (2:1 ratio). Demographic, risk factor, and clinical data were collected prospectively. TOAST subtypes were assigned. Admission brain MRIs were used to assess infarct size and location. Multivariate logistic regression model for variables showing univariate association with cocaine use at p <0.2 was used to identify independent predictors of cocaine-associated AIS. Results: Between 2007-2010, we identified 91 cases and 182 controls (mean age 50.1±10.4 years; 73.6% male). Cases did not statistically differ from controls by income ($49,499 ±15,494 vs. $51,818±16,776), occupation (52% in “service/clerical”), or educational level (42.5% high-school graduates)(all p>0.5). Stroke severity was similar in both groups (median NIHSS 5, IQR 1-8 vs. 5.7, IQR 1-8, p=0.3) as was acute DWI volume (median 33.6cc, IQR 5-20 vs. 21.2cc, IQR 5-20; p=0.5), and proportion of patients treated with IV tPA (12% vs. 17%, p=0.4). Active tobacco use was significantly greater in cocaine-associated AIS (84% vs. 6%, p< 0.001). In multivariable analysis, tobacco use (OR 3.9, 95% CI 2.0-7.5), history of migraine (OR 2.5, 95% CI 1.1-5.9), and cardioembolic stroke subtype (OR 2.52, 95% CI 0.6-0.9) were independent predictors of cocaine-associated AIS. Subset analysis of toxicology confirmed (“active”) cocaine users (n=29) with AIS compared to non-cocaine using controls (n=58) from the same population. Association between cardioembolic stroke subtype (p<0.004) persisted. Active tobacco use emerged as a robust predictor of cocaine-associated stroke (OR 12.9, 95%CI 3.7-44.4) in this subset. Conclusions: Active tobacco use is an independent predictor of stroke among both active and past cocaine users. Stroke prevention campaigns should target broader audiences for smoking cessation and cocaine use prevention.