In the absence of clinical trials, the benefit of endovascular therapy (EVT) on the treatment of acute ischemic stroke (AIS) with primary distal and medium vessel occlusions (DMVO) is still not well defined. The aim of the study is to evaluate EVT with or without intravenous thrombolysis (EVT ± IVT) in primary DMVO stroke in comparison with a control cohort treated with IVT alone. We analysed all consecutive AIS with proven primary DMVO. Primary endpoints were excellent outcome, functional independence at 3 months follow-up, and early neurologic improvement at 1 day after treatment. One hundred and fourteen patients with DMVO strokes were included between 2019 and 2023. Propensity-weighted analysis showed no significant differences in EVT ± IVT vs IVT for the excellent outcome (adjusted OR [aOR], 1.575; 95% CI, 0.706-3.513), functional independence (aOR, 2.024; 95% CI, 0.845-4.848), early neurological improvement (aOR, 2.218; 95% CI, 0.937-5.247), mortality (aOR, 0.498; 95% CI, 0.177-1.406), symptomatic intracranial haemorrhage (aOR, 0.493; 95% CI, 0.102-2.385), and subarachnoid haemorrhage (aOR, 0.560; 95% CI, 0.143-2.187). The type of revascularization did not influence the percentage of cerebral volume lost (adjusted linear regression estimate, -19.171, t value, 11.562; p = 0.104). This study supports the hypothesis that patients with primary DMVO stroke treated with EVT (±IVT) or IVT alone have comparable outcomes.