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Introduction: In intracranial medium-vessel occlusions (MeVOs), intravenous thrombolysis (IVT) shows inconsistent effectiveness and endovascular interventions remains unproven. We evaluated a new therapeutic strategy based on a second IVT using tenecteplase for MeVOs without early recanalization post-alteplase.Patients and methods: This retrospective, comparative study included consecutively low bleeding risk MeVO patients treated with alteplase 0.9 mg/kg at two stroke centers. One center used a conventional single-IVT approach; the other applied a dual-IVT strategy, incorporating a 1-h post-alteplase MRI and additional tenecteplase, 0.25 mg/kg, if occlusion persisted. Primary outcomes were 24-h successful recanalization for efficacy and symptomatic intracranial hemorrhage (sICH) for safety. Secondary outcomes included 3-month excellent outcomes (modified Rankin Scale score of 0–1). Comparisons were conducted in the overall cohort and a propensity score-matched subgroup.Results: Among 146 patients in the dual-IVT group, 103 failed to achieve recanalization at 1 h and of these 96 met all eligible criteria and received additional tenecteplase. Successful recanalization at 24 h was higher in the 146 dual-IVT cohort patients than in the 148 single-IVT cohort patients (84% vs 61%, p< 0.0001), with similar sICH rate (3 vs 2, p= 0.68). Dual-IVT strategy was an independent predictor of 24-h successful recanalization (OR, 2.7 [95% CI, 1.52–4.88]; p< 0.001). Dual-IVT cohort patients achieved higher rates of excellent outcome (69% vs 44%, p< 0.0001). Propensity score matching analyses supported all these associations.Conclusion: In this retrospective study, a dual-IVT strategy in selected MeVO patients was associated with higher odds of 24-h recanalization, with no safety concerns. However, potential center-level confounding and biases seriously limit these findings’ interpretation.Trial Registration ClinicalTrials.gov Identifier: NCT05809921