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Reports of community-associated methicillin-resistant Staphylococcus aureus(CA-MRSA) in neonatal intensive care units (NICU) and in otherwise healthy patients without obvious risk factors have been increasing in frequency. Described herein is a cluster of cases of CA-MRSA USA300 strains in an NICU affecting infants, health-care workers and the health-care workers' families.Infants and health-care workers with infection and colonization due to MRSA between 1 January 2004 and 30 June 2005 in a tertiary care center NICU in San Antonio, TX were studied. Antimicrobial susceptibility testing and polymerase chain reaction detection of the mecA gene characterized the MRSA isolates. All MRSA cases were reviewed for clinical severity of infection and outcome.During the 18 months studied, a total of four (0.6%) of 676 infants had CA-MRSA bacteremia or colonization. One infant with necrotizing pneumonia died and three health-care workers who directly cared for the infected infants developed soft-tissue infections caused by CA-MRSA. Four family members of two health-care workers subsequently developed soft-tissue infections. All of the analyzed isolates (eight of nine) belonged to pulsed-field type USA300 and possessed Panton–Valentine leukocidin genes, which have been associated with severe skin and soft-tissue infections, and necrotizing pneumonia.It is likely that the CA-MRSA USA300 strain can be transmitted between NICU patients to health-care workers and their family members. The CA-MRSA cases reported here reinforce the virulence of CA-MRSA USA300 strains and emphasize the need to embrace infection control practices designed to protect hospitalized patients, health-care workers and their family members.