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Despite being the standard of care, thrombolytic therapy with tissue plasminogen activator (t-PA) is currently administered to only 5% of acute ischemic stroke (AIS) patients in the United States. Published scientific information regarding both the use of t-PA for AIS in Hispanic patients and its impact on short-term mortality is scarce. The objectives of this study are to investigate, among Puerto Rican patients hospitalized with AIS, the rate of t-PA administration, and the risk of in-hospital mortality in patients who received t-PA vs. those patients who did not receive t-PA.We performed a secondary analysis of data from patients with AIS admitted to acute care facilities throughout Puerto Rico in study years 2007, 2009, and 2011who were participating in the Puerto Rico Cardiovascular Disease Surveillance System. Multivariate logistic regression was used to determine the independent association between treatment with t-PA within 4.5 hours of symptom onset and in-hospital mortality.Of the 1968 study patients hospitalized with AIS, 104 (5%) received t-PA treatment. After adjustments for demographic and clinical confounders, patients receiving t-PA had similar odds of in-hospital mortality as patients not receiving t-PA did (OR = 2.49, 95% CI = 0.81-7.66). The receipt of concomitant anticoagulation medication was independently associated with relatively lower odds of in-hospital mortality (OR = 0.42, 95% CI = 0.20-0.88). Being over 80 years of age (OR = 2.03, 95% CI = 1.13-3.68), being obese (OR = 1.88, 95% CI = 1.01-3.49), and arriving in an ambulance (OR = 3.61, 95% CI = 1.95-6.68) were all independently associated with relatively higher odds of in-hospital mortality.Among patients hospitalized in Puerto Rico with acute ischemic stroke, t-PA treatment was not significantly associated with in-hospital mortality.