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Background About 25% of patients with acute ischemic stroke have lacunar infarct on follow‐up imaging. In this secondary analysis from the AcT (Alteplase Compared With Tenecteplase) trial, we assessed if there is variation in safety or efficacy of intravenous thrombolysis by infarct type in patients with no visible occlusion. We also determined if this effect differed between tenecteplase and alteplase. Methods and Results This is a secondary analysis from the AcT trial. Lacunar infarct was defined as single, ≤15 mm, and in regions supplied by perforating arterioles on 24‐hour imaging. Outcomes included symptomatic intracerebral hemorrhage at 24 hours, any hemorrhage on imaging, and 90‐day modified Rankin Scale score. Mixed‐effects regression models adjusted for age, sex, stroke severity, thrombolytic type, and onset‐to‐needle time were used. Of 1577 patients, 456/29.9% had no visible occlusion and interpretable follow‐up imaging (magnetic resonance imaging: 41.2%). Of these 93 (20.4%) (magnetic resonance imaging: 62.3%) had lacunar infarct, 171 (37.5%) (magnetic resonance imaging: 67.4%) had nonlacunar infarct, and 192 (42.1%) (magnetic resonance imaging: 7.3%) had no visible infarct. Four patients (2.3%) in the group with nonlacunar infarct and none in the groups with lacunar infarct and no visible infarct developed symptomatic intracerebral hemorrhage. Any intracranial hemorrhage was highest (21; 12.4%) in the group with nonlacunar infarct. There was no significant interaction between thrombolytic type and treatment outcomes. Conclusions In the AcT trial, safety of intravenous thrombolysis was similar across all infarct types in patients with no visible occlusion but functional outcomes were worst in patients with nonlacunar infarct. Safety and functional outcomes after intravenous thrombolysis were better in the groups with lacunar infarct and no visible infarct as compared with the overall trial population.