Background and Purpose: Patients with intracerebral hemorrhage (ICH) have oxidative stress. Oxidative stress contributes to the development and progression of perihematomal edema (PHE) in brain hemorrhage patients. We hypothesized that reactive oxygen species (ROS) scavengers might have a neuroprotective role in the acute period of patients with ICH. Methods: This prospective, multicenter, single-blind, randomized study was conducted between June 2017 and October 2019. Intracranial bleeding, including spontaneous ICH, secondary ICH due to vascular anomalies, venous thrombosis, neoplasms, or hemorrhagic infarction, were included in our study. These ROS scavengers were given for 14 days with a dose of N-acetylcysteine 2000 mg/d and selenium 1600 µg/d intravenously. Other patients received a placebo. The primary outcome was hemorrhage and PHE volume changes in 2-week follow-up computed tomography between ROS scavenger versus placebo groups. Results: In total, 448 patients were enrolled with 123 patients remaining after applying the inclusion and exclusion criteria. There were no significant differences in baseline characteristics between the ROS scavenger (n=57) and placebo (n=66) groups. No significant differences in baseline hematoma and PHE volumes were observed but 2 weeks follow-up computed tomography showed significant differences in PHE volume (21.90±17.63 versus 30.66±32.35, P <0.01) and PHE ratio (1.19±0.73 versus 2.05±1.27, P <0.01). Among clinical factors, time to reach target Richmond Agitation Sedation Scale (5.98 hours [95% CI, 4.82–7.241 versus 8.42 hours], [95% CI, 6.57–10.77], P <0.01) and the length of intensive care unit stays (6.46 days [95% CI, 2.38–10.55 versus 12.66 days], [95% CI, 8.47–16.85], P <0.01) were significantly shortened among patients who received ROS scavengers than among patients who did not receive ROS scavenger. Conclusions: ROS scavenger showed a significantly reduced PHE volume, time to reach target Richmond Agitation Sedation Scale, and shortened length of intensive care unit stay in patients with acute ICH. Early and high doses of ROS scavengers in a combination regimen may have played a key role in obtaining a favorable outcome in our study. Registration: URL: https://cris.nih.go.kr/cris/en ; Unique identifier: KCT0004628.