Although elevated blood pressure (BP) is very common in patients with acute ischemic stroke, the management of hypertension among them remains controversial. We tested the effect of immediate BP reduction on two-year mortality and major disability in acute ischemic stroke patients. The China Antihypertensive Trial in Acute Ischemic Stroke, a randomized, single-blind, blinded end-points trial, was conducted in 4,071 patients with ischemic stroke within 48 hours of onset and elevated systolic BP (SBP). Patients were randomly assigned to receive antihypertensive treatment (n=2,038) or to discontinue all antihypertensive medications (n=2,033) during hospitalization. Post-treatment follow-ups were conducted at 3, 12, and 24 months after hospital discharge. The primary outcome was a composite of death and major disability at the two-year follow-up visit. Mean SBP was reduced by 21.8 in the treatment group and 12.7 mm Hg in the control group within 24 hours after randomization (P<0.001). Mean SBP was 137.3 mm Hg in the treatment group and 146.5 in the control group at day 7 after randomization (P<0.001). At two-year follow-up, study outcomes were obtained in 1945 (95.4%) participants in the treatment group and 1925 (94.7%) in the control group. 78.8% of the patients in the treatment group and 72.6% in the control group reported the use of antihypertensive medications (p<0.001). SBP was 138.8 mmHg in the antihypertensive treatment group and 139.7 in the control group (p=0.02). Among patients in the antihypertensive treatment group, 24.5% (476/1945) died or had a major disability, compared with 22.1% (425/1925) in the control group (odds ratio 1.14 [95% CI 0.99 to 1.33], p=0.078). Hazard ratios for all-cause mortality (1.01 [0.81, 1.25], p=0.95), recurrent stroke (0.91 [0.73, 1.13], p=0.40), and vascular events (0.97 [0.79, 1.19], p=0.76) were not statistically significant comparing the antihypertensive treatment group to the control group. The effect of antihypertensive treatment did not differ by pre-defined subgroups. In conclusion, among patients with acute ischemic stroke, BP reduction with antihypertensive medications during hospitalization did not reduce or increase the composite outcome of death and major disability over two years.