BACKGROUND AND PURPOSE—We aimed to determine whether subjects aged ≤70 years who were treated with intravenous glyburide (RP-1127; BIIB093; glibenclamide) would have better long-term outcomes than those who received placebo. METHODS—GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke–Remedy Pharmaceuticals) was a prospective, double-blind, randomized, placebo-controlled phase 2 clinical trial. Eighty-six participants, aged 18 to 80 years, who presented to 18 centers with large hemispheric infarction (baseline diffusion-weighted imaging volumes, 82–300 cm) randomized within 10 hours of symptom onset were enrolled. In the current exploratory analysis, we included participants aged ≤70 years treated with intravenous glyburide (n=35) or placebo (n=30) who met per-protocol criteria. Intravenous glyburide or placebo was administered in a 1:1 ratio. We analyzed 90-day and 12-month mortality, functional outcome (modified Rankin Scale, Barthel Index), and quality of life (EuroQol group 5-dimension). Additional outcomes assessed included blood–brain barrier injury (MMP-9 matrix metalloproteinase 9) and cerebral edema (brain midline shift). RESULTS—Participants ≤70 years of age treated with intravenous glyburide had lower mortality at all time points (log-rank for survival hazards ratio, 0.34; P=0.04). After adjustment for age, the difference in functional outcome (modified Rankin Scale) demonstrated a trend toward benefit for intravenous glyburide-treated subjects at 90 days (odds ratio, 2.31; P=0.07). Repeated measures analysis at 90 days, 6 months, and 12 months using generalized estimating equations showed a significant treatment effect of intravenous glyburide on the Barthel Index (P=0.03) and EuroQol group 5-dimension (P=0.05). Participants treated with intravenous glyburide had lower plasma levels of MMP-9 (189 versus 376 ng/mL; P<0.001) and decreased midline shift (4.7 versus 9 mm; P<0.001) compared with participants who received placebo. CONCLUSIONS—In this exploratory analysis, participants ≤70 years of age with large hemispheric infarction have improved survival after acute therapy with intravenous glyburide. CLINICAL TRIAL REGISTRATION—URLhttps://www.clinicaltrials.gov. Unique identifierNCT01794182.