We report the case of a 64-year-old man with Arcanobacterium pyogenes endocarditis. The patient presented with dyspnea and asymmetrical progressive quadriparesis. A transthoracic echocardiogram revealed mobile vegetations on both leaflets of his mitral valve measuring 0.5 x 3 cm, thickening of the mitral valve with severe mitral regurgitation due to dehiscence of the papillary muscle to the posterior mitral leaflet. He also had aortic sclerosis with a vegetation measuring 0.5 x 1 cm causing aortic valve dehiscence and free flow aortic regurgitation. An initial hemoculture grew out pleomorphic, gram-positive, non-motile, anaerobic to microaerophilic bacilli. A diagnosis of infective endocarditis was made using modified Duke criteria. He was treated with intravenous ampicillin and gentamicin. Four days after admission, he developed acute respiratory failure and succumbed to the disease. A pre-mortem hemoculture and post-mortem heart valve culture grew Arcanobacterium pyogenes. Septic thromboemboli involving the brain, kidneys, lungs and spleen were documented. The patient also had ischemic vasculopathy with focal spinal arteriolitis and bilateral demyelination of the cervical corticospinal tracts. There are three published reports of human A. pyogenes endocarditis in the literature. Neurological involvement with ischemic spinal vasculopathy and demyelination has not been reported. We report the first autopsy proven case of A. pyogenes infective endocarditis with ischemic spinal vasculopathy. We review the clinicopathologic features of systemic A. pyogenes infection.