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Active substance use (ASU) increases global mortality and cerebrovascular risk, yet its impact on outcomes after mechanical thrombectomy (MT) for large-vessel occlusive acute ischemic stroke (LVO-AIS) remains unclear. We evaluated the association between ASU and procedural and clinical outcomes following MT at a large urban comprehensive stroke center.We retrospectively analyzed a prospectively maintained registry of anterior-circulation LVO-AIS patients treated with MT between 2005 and 2024. Adults with available historical or toxicology-confirmed substance use data were included. ASU was defined as use of alcohol, tobacco, cannabis, cocaine, heroin, or amphetamines. The primary outcome was 90-day modified Rankin Scale (mRS). Secondary outcomes included 24-hour NIHSS, symptomatic intracranial hemorrhage (sICH), successful reperfusion (mTICI 2b-3), length of stay, and procedural complications. Statistical comparisons used t-tests and chi-squared or Fisher’s exact tests.Among 3,855 screened cases, 3,662 were included. Alcohol use was associated with higher rates of successful reperfusion (52.4% vs. 30.3%, p < 0.0001) and modestly improved 90-day mRS (p < 0.001). Tobacco use was similarly associated with slightly better 90-day functional outcomes without differences in secondary outcomes. In contrast, opioid use was associated with worse neurologic outcomes, including higher 24-hour NIHSS (p = 0.002) and worse 90-day mRS (p = 0.004).ASU demonstrated substance-specific associations with post-MT outcomes. Alcohol and tobacco use correlated with improved reperfusion or recovery, whereas opioid use was associated with poorer neurologic outcomes, warranting further investigation.Disclosures G. Karayi: None. E. Shaaya: None. K. Moldovan: None.