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Background Medium and distal vessel occlusions (MeVO/DMVO) account for approximately 25-40% of acute ischemic strokes and are associated with significant neurological disability despite often presenting with lower NIHSS scores. Early recanalization prior to endovascular therapy may improve outcomes and reduce procedural complexity. tenecteplase has pharmacologic advantages over alteplase, including greater fibrin specificity and longer half-life, which may enhance early clot dissolution and spontaneous recanalization before thrombectomy. However, comparative data evaluating spontaneous recanalization between these agents in MeVO/DMVO strokes remain limited.Methods We conducted a retrospective cohort study of consecutive adults with acute ischemic stroke due to medium or distal vessel occlusion treated with intravenous thrombolysis followed by mechanical thrombectomy at our institution between January 2021 and March 2025. Patients received either intravenous alteplase or tenecteplase according to institutional protocols. Baseline demographics, procedural characteristics, angiographic outcomes, and time metrics were compared. Spontaneous recanalization prior to thrombectomy was assessed using diagnostic angiography. Functional outcomes were measured using the modified Rankin Scale (mRS) at discharge and 90 days. Multivariable logistic regression was performed to identify predictors of functional outcomes.Results A total of 101 patients were included (alteplase n=55; tenecteplase n=46). Spontaneous recanalization prior to thrombectomy occurred more frequently in patients treated with tenecteplase compared with alteplase (32% vs 24%), although this difference did not reach statistical significance. Baseline demographics were otherwise similar, though baseline NIHSS was higher in the tenecteplase group (13.0 vs 11.2, P=0.029). Procedural time metrics, number of thrombectomy passes, and first-pass effect rates were comparable. Successful reperfusion (mTICI 2b-3) was achieved in 90% of alteplase-treated patients and 96% of Tenecteplase-treated patients. Good functional outcome (mRS 0-2) occurred in 50% vs 55% at discharge and 59% vs 70% at 90 days in the alteplase and tenecteplase groups, respectively. In adjusted analysis, tenecteplase was associated with higher odds of good functional outcome at 90 days, while older age, longer door-to-puncture time, and higher discharge NIHSS predicted worse outcomes.Conclusions Tenecteplase demonstrated a numerically higher rate of spontaneous recanalization compared with alteplase in patients with MeVO/DMVO stroke undergoing thrombectomy, with comparable safety and reperfusion outcomes and improved adjusted functional outcomes at 90 days. These findings suggest that tenecteplase may facilitate early clot dissolution in distal occlusions and support further prospective investigation.Disclosures M. Jatty: None. P. Pitchan Velammal: None. M. Elnaeim: None. J. Jones: None.Abstract E-195 Figure 1