<b><i>Objective:</i></b> To determine the extent to which the effects of intensive blood pressure (BP) lowering are modified by doses of alteplase in thrombolysis-eligible acute ischemic stroke (AIS) patients. <b><i>Methods:</i></b> Prespecified analyses of the Enhanced Control of Hypertension and Thrombolysis Stroke Study for patients enrolled in both arms: (i) low-dose (0.6 mg/kg body weight) or standard-dose (0.9 mg/kg) alteplase and (ii) intensive (target systolic BP [SBP] 130–140 mm Hg) or guideline-recommended (target SBP &#x3c;180 mm Hg) BP management. The primary outcome was functional recovery, measured by a shift in scores on modified Rankin scale at 90 days. The safety outcome was any intracranial hemorrhage (ICH). <b><i>Results:</i></b> There were 925 participants (mean age 67 years, 39% female, 77% Asian) randomized to both arms: 242 randomly assigned to guideline/standard-dose (GS); 234 to guideline/low-dose (GL); 227 to intensive/standard-dose (IS); and 222 to intensive/low-dose (IL). Overall, average SBP levels within 24 h were lower in the low-dose compared to standard-dose alteplase group (146 and 144 vs. 151 and 150 mm Hg, for GS and GL vs. IS and IL, respectively, <i>p</i> &#x3c; 0.0001). There was no heterogeneity of the effects of BP lowering (intensive vs. guideline) on functional recovery between standard-dose (OR 0.81, 95% CI 0.59–1.12) and low-dose alteplase (1.06, 0.77–1.47; <i>p</i> = 0.25 for interaction). Similar results were observed for ICH (<i>p</i> = 0.50 for interaction). <b><i>Conclusions:</i></b> In thrombolysis-treated patients with predominantly mild-to-moderate severity AIS, intensive BP lowering neither improve functional recovery, either with low- or standard-dose intravenous alteplase, nor beneficially interact with low-dose alteplase in reducing ICH. <b><i>Trial Registration:</i></b> The trial is registered with ClinicalTrials.gov (NCT01422616).