AIMS: The objective of this descriptive study was to compare time to medical evaluation, intravenous tissue plasminogen activator (IV tPA) use, and short-term outcomes in illicit drug users compared to non-users presenting with acute ischemic stroke (AIS). STUDY DESIGN: This is a retrospective study performed from our stroke registry using deidentified patient information. PLACE AND DURATION OF STUDY: Tulane Medical Center Primary Stroke Center (PSC). Consecutive AIS patients presenting to our PSC from July 2008 to December of 2010 were identified from our prospectively collected stroke registry. METHODOLOGY: Patients were categorized as toxicology positive (TP) or toxicology negative (TN). We compared baseline characteristics, clinical presentation, tPA use, and short-term outcomes in TP and TN patients. RESULTS: Two hundred and sixty-three patients met inclusion criteria (median age 63, 35.4% female, 66.5% Black). Nearly 40% of toxicology screens were positive. Stroke severity was similar with the median National Institute of Health Stroke Scale (NIHSS) of 6 in both groups; however, a higher proportion of TN patients were treated with IV tPA (32.1% vs. 21.2%). After adjustment for time from last seen normal to emergency department arrival (LSN-to-ED arrival), the odds of being treated with tPA for TP patients were similar to TN patients (OR 0.69, 95% CI 0.36-1.31, p=0.255). After adjustment for age, NIHSS, glucose, and tPA, the odds of in-hospital mortality in TP patients was 3 times that of TN patients (OR 3.17, 95% CI 1.07-9.43, p=0.038). CONCLUSION: We found that the disparities observed in tPA use were attenuated after adjustment for time from LSN-to-ED arrival, suggesting an area for future intervention. Additionally, we found that TP patients may be at higher risk for in-hospital mortality. Further study on the role of substance abuse in time to ED arrival, tPA use, and outcome in AIS patients is warranted.