Sore, cracked nipples are commonly experienced by breastfeeding mothers. We have previously reported a strong correlation between sore, cracked nipples and S. aureus colonization. A prospective, randomized clinical trial was performed to compare four treatment regimes for S. aureus infected sore nipples. Eighty-four breastfeeding mothers were enrolled in the study. After 5 days to 7 days of treatment, only 8% of mothers showed improvement in the "optimal breastfeeding technique alone" group, 16% improved with topical mupiricin, 29% improved with topical fusidic acid, yet 79% improved with oral antibiotics (p < .0001). Optimal breastfeeding techniques and topical antibiotics ointment failed to heal most infected, sore, cracked nipples. Mastitis developed in 12% to 35% of mothers not treated with systemic antibiotics compared to 5% of mothers treated with systemic antibiotics (p < .005). In conclusion, S. aureus infected sore, cracked nipples should be diagnosed as a potentially widespread impetigo vulgaris and treated aggressively with systemic antibiotics in order to improve healing and decrease the risk of developing mastitis due to an ascending lactiferous duct bacterial infection.