After reperfusion therapy in stroke patients secondary inflammatory processes may increase cerebral damage. In this pilot study, effects of anti-inflammatory therapy were assessed in a middle cerebral artery occlusion (MCAO) mouse model after reperfusion. 1 hour after MCAO, the artery was reopened and tacrolimus or NaCl were administered intra-arterially. Perfusion-weighted (PWI) and diffusion-weighted images (DWI) were obtained by MRI during MCAO. DWI, T2- and T1-weighted images with and without Bis-5HT-DTPA administration were obtained 24 hours after MCAO. Neutrophils, Myeloperoxidase-positive-(MPO+)-cells and microglia, including M1 and M2 phenotypes, were assessed immunohistochemically. Treatment with tacrolimus led to significantly smaller apparent diffusion coefficient (ADC) lesion volume within 24 hours (median -55.6mm(3), range -81.3 to -3.6, vs. median 8.0 mm(3), range 1.2 to 41.0; P = 0.008) and significantly lower enhancement of Bis-5-HT-DTPA (median signal intensity (SI) ratiocortex, median 92.0%, range 82.8% to 97.1%, vs. median 103.1%, range 98.7% to 104.6%; P = 0.008) compared to the NaCl group. Immunohistochemical analysis showed no significant differences between both groups. Intra-arterially administered anti-inflammatory agents after mechanical thrombectomy may improve treatment efficiency in stroke by reducing infarct volume size and MPO activity.