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To evaluate race differences in tissue plasminogen activator (tPA) refusal among eligible patients with acute ischemic stroke (AIS) in Chicago.Using the Get With The Guidelines–Stroke registry data from 15 primary stroke centers between January 2013 and June 2015, we performed a retrospective analysis of patients with AIS presenting to the emergency department within 4.5 hours from symptom onset. Patient or proxy refusal was captured as a reason for nonadministration of tPA to eligible patients in the registry. We assessed whether tPA refusal differed by race using logistic regression.Among 704 tPA-eligible patients with AIS, tPA was administered to 86.2% (black race, 82.5% vs nonblack race, 89.5%; p < 0.001). Fifty-three (7.5%) tPA refusals were documented. Refusal was more common in black vs nonblack patients (10.6% vs 4.8%; p = 0.004). In multivariable analysis, the following were associated with tPA refusal: black race (adjusted odds ratio [OR] 2.5, 95% confidence interval [CI] 1.3–4.6), self-pay status (adjusted OR 3.23, 95% CI 1.2–8.71), prior stroke (adjusted OR 2.11, 95% CI 1.14–3.90), age (adjusted OR 1.04, 95% CI 1.02–1.07), and NIH Stroke Scale score (adjusted OR 0.94, 95% CI 0.90–0.99).Among tPA-eligible patients with AIS in Chicago, over 7% refused tPA. Refusal was more common in black patients and accounted for the apparent lower rates of tPA use in black vs nonblack patients. Further research is needed to understand barriers to consent and overcome race–ethnic disparities in tPA treatment for AIS.