Background We explored the influence of low-dose intravenous alteplase and intensive blood pressure lowering on outcomes of acute ischemic stroke according to status/location of vascular obstruction in participants of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Methods ENCHANTED was a multicenter, quasi-factorial, randomized trial to determine efficacy and safety of low- versus standard-dose intravenous alteplase and intensive- versus guideline-recommended blood pressure lowering in acute ischemic stroke patients. In those who had baseline computed tomography or magnetic resonance imaging angiography, the degree of vascular occlusion was grouped according to being no (NVO), medium (MVO), or large (LVO). Logistic regression models were used to determine 90-day outcomes (modified Rankin scale [mRS] shift [primary], other mRS cut-scores, intracranial hemorrhage, early neurologic deterioration, and recanalization) by vascular obstruction status/site. Heterogeneity in associations for outcomes across subgroups was estimated by adding an interaction term to the models. Results There were 940 participants: 607 in alteplase arm only, 243 in blood pressure arm only, and 90 assigned to both arms. Compared to the NVO group, functional outcome was worse in LVO (mRS shift, adjusted OR [95% CI] 2.13 [1.56–2.90]) but comparable in MVO (1.34 [0.96–1.88]) groups. There were no differences in associations of alteplase dose or blood pressure lowering and outcomes across NVO/MVO/LVO groups (mRS shift: low versus standard alteplase dose 0.84 [0.54–1.30]/0.48 [0.25–0.91]/0.99 [0.75–2.09], P_interaction = 0.28; intensive versus standard blood pressure lowering 1.32 [0.74–2.38]/0.78 [0.31–1.94]/1.24 [0.64–2.41], P_interaction = 0.41), except for a borderline significant difference for intensive blood pressure lowering and increased early neurologic deterioration (0.63 [0.14–2.72]/0.17 [0.02–1.47]/2.69 [0.90–8.04], P_interaction = 0.05). Conclusions Functional outcome by dose of alteplase or intensity of blood pressure lowering is not modified by vascular obstruction status/site according to analyses from ENCHANTED, although these results are compromised by low statistical power. Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifiers: NCT01422616