The effects of enzalutamide monotherapy on prostate tumor downsizing and multiparametric MRI are currently unknown. Here we present the first case in literature of a patient with high-grade prostate cancer who underwent 3 months of neoadjuvant enzalutamide, for which the effects on mpMRI and histology were determined. Tumor size reduction and downstaging were noted. Neoadjuvant enzalutamide resulted in an increase in ADC value on the DWI-MRI sequences. Histological changes were also observed.