Although neonatal infections caused by Streptococcus viridans have been suggested to be less severe than those caused by classic neonatal pathogens, little is known about neonatal infections caused by specific species within this group of bacteria. We report six infants who had S. mitis isolated from blood culture. All were infected at < or = 3 days of age; five of the mothers had perinatal risk factors for neonatal sepsis. Five infants were preterm and three had birth weights < or = 2500 gm. Hematologic abnormalities were common. Two died as a result of the infection. Antibiotic susceptibility testing of four isolates revealed resistance to penicillin and ampicillin in three and resistance to gentamicin in two. In vivo resistance was not observed. S. mitis is not part of normal skin flora, should not be assumed to be a contaminant, and can cause severe neonatal disease. If S. mitis or S. viridans are recovered from a normally sterile body site and the patient fails to improve with penicillin therapy, it seems prudent to switch to vancomycin until susceptibility results are available.