Re-occlusion and intravascular thrombus formation following mechanical thrombectomy (MT) in stroke patients worsen clinical outcomes. Although early administration of antiplatelet therapy (APT) prevents these complications, current guidelines advise against using APT soon after intravenous thrombolysis (IVT), making the management of atherothrombotic large vessel occlusion (AT-LVO) difficult. We investigated the safety of early APT for acute AT-LVO treated with MT following IVT. This post-hoc analysis of a registry study of 770 AT-LVO patients treated with MT across 51 institutions in Japan from January 2017 to December 2019, specifically targeted patients with anterior circulation AT-LVO. Safety endpoints were symptomatic intracranial hemorrhage (sICH), any intracranial hemorrhage (ICH), all hemorrhagic events and mortality at 90 days. The endpoints between patients in whom APT was initiated before or during MT (pre-/intra-MT APT group) and those with APT initiation after MT or treated without APT (post-MT/no APT group) were compared before and after propensity score-matching. Of the 164 patients included in the study (120 males, age 72 ± 11 years), 84 and 80 patients were included in each group. In the propensity score-matched cohort (37 patients each), the rate of all hemorrhagic events (14 vs. 22 %, p = 0.359), any ICH (8 vs. 14 %, p = 0.711), sICH (3 vs. 8 %, p = 0.615), and mortality (3 vs. 3 %, p = 1.000) did not differ significantly between the two groups. Early APT following IVT in acute AT-LVO treated with MT might be safe.