Penicillin-resistant viridans group streptococci (VGS) infections are an emerging issue in infectious diseases. Here, we present a case of mitral valve infective endocarditis caused by highly penicillin-resistant VGS (minimum inhibitory concentration >4 μg/mL), which was successfully treated with daptomycin. Although the clinical efficacy of daptomycin has not been established, it can be an alternative for the treatment of highly resistant VGS endocarditis.