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Recombinant tissue-type plasminogen activator (rtPA) is the only approved therapy for acute ischemic stroke (AIS). In 2004, 1.8% to 2.1% of AIS patients in the United States received rtPA. Given incentives from regulatory agencies and payors to increase rtPA use, we hypothesized that rtPA use in the United States would increase from 2005 to 2009.AIS cases were defined by exclusion of hemorrhagic stroke and transient ischemic attack International Classification of Diseases 9th revision codes (430, 431, 432, and 435) from diagnosis-related groups 14, 15, 524, and 559 discharges. Patients receiving thrombolytics were identified using International Classification of Diseases 9th revision code 99.10 (Medicare Provider and Analysis Review and Premier databases) and pharmacy billing records (Premier). Change over time and differences between databases were tested using negative binomial regression.Within Medicare Provider and Analysis Review, thrombolytic use increased from 1.1% in 2005 to 3.4% in 2009 (P<0.001 for trend). Within Premier, thrombolytic use increased from 1.4% in 2005 to 3.7% in 2009 for all cases (P<0.001). Analysis of pharmacy billing records in Premier for 50-mg or 100-mg doses of rtPA showed that 3.4% of AIS cases were treated in 2009. Inclusion of patients with transient ischemic attack or hemorrhagic stroke International Classification of Diseases 9th revision codes who received any thrombolytic as “ischemic stroke patients receiving rtPA” changed the rate of thrombolysis to 5.2%.In 2009, 3.4% to 5.2% of AIS patients in the United States received thrombolytics, approximately double the rate of treatment in 2005. Rapid recognition and transport and quick treatment in the emergency department remain goals for further improving treatment rates.