• The first randomized trial to test the effect of immediate BP reduction on the risk of PSD in acute ischemic stroke patients. • Early antihypertensive treatment did not result in a significant reduction in the risk of PSD among ischemic stroke patients. • The decision to decrease BP in patients with acute ischemic stroke should be based on individual clinical judgment. Several prospective studies have identified that hypertension is an important risk factor of post-stroke depression (PSD). However, the effect of immediate antihypertensive treatment on the risk of PSD in patients with acute ischemic stroke remains unknown. In this prespecified depression substudy of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) randomized clinical trial, a total of 642 patients with acute ischemic stroke within 48 h of onset and elevated systolic BP at 7 sites of CATIS were included. Patients were randomly assigned to receive antihypertensive treatment ( n = 318) or to control group ( n = 324). The primary outcome was depression (Hamilton Rating Scale for Depression score≥8) at 3-month posttreatment follow-up. At 24 h after randomization, the mean systolic BP was reduced by 21.6 mm Hg (12.5%) in the treatment group and 13.9 mm Hg (7.9%) in the control group (difference, -7.7 mm Hg [95% CI, -10.2 to -5.2]; P <0.001). The mean systolic BP levels at 7 days ( P <0.001) and 14 days ( P <0.001) after randomization in treatment group were also significantly lower than those in control group. At 3-month posttreatment follow-up, 122 patients (38.4%) in antihypertensive treatment group and 131 patients (40.4%) in control group developed PSD (odds ratio, 0.92 [95% CI, 0.67 to 1.26]; P = 0.59). All patients in the CATIS trial were Chinese, which might limit the generalizability of our findings to other populations. Early antihypertensive treatment had no effect on the risk of PSD at 3 months among patients with acute ischemic stroke and elevated BP.