Headache during or soon after administration of IV tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) is a concern for hemorrhagic transformation (HT). However, no data are available regarding the incidence of HT in these patients or the prognostic indication of these headaches. We examine the importance of tPA-associated headaches among AIS patients in terms of HT rates and clinical outcomes. AIS patients treated with IV tPA at a comprehensive stroke center between January 2007 and November 2012 were retrospectively reviewed for documented tPA-associated headache in the first 24 hours post-tPA. We compared the headache and nonheadache groups for differences in various clinical and radiologic outcomes. Of the 193 patients, 63 (32.6%) had tPA-associated headache. Headache patients (HP) were younger than nonheadache patients (NHP) (mean ± SD, 59.5 ± 17.4 years vs 69.9 ± 15.5 years, < 0.0001), and 53% of HP were men, compared to 49.2% of NHP ( = 0.537). Comorbid conditions did not differ between the 2 groups. There were no statistical differences between HP and NHP in admission NIH Stroke Scale (NIHSS) score (11.2 ± 5.7 vs 11.5 ± 5.5, = 0.646), NIHSS score at 24 hours (6.5 ± 5.7 vs 7.4 ± 6.9, = 0.466), NIHSS score at discharge (6.7 ± 10.1 vs 8.1 ± 11.6, = 0.448), HT (12.7% vs 18.4%, = 0.3), cervical artery dissection (4.7% vs 5.38%, = 0.764), length of hospitalization (6.29 ± 5 days vs 6.35 ± 4.7 days, = 0.935), and disposition. tPA-associated headache does not predict increased risk of HT and has no other prognostic importance in patients with AIS. Prospective studies with a larger cohort may be needed to further explore this relationship.