Staphylococcus aureus organisms vary in the function of the staphylococcal virulence regulator gene agr. To test for a relationship between agr and transmission in S. aureus, we determined the prevalence and genetic basis of agr dysfunction among nosocomial methicillin-resistant S. aureus (MRSA) in an area of MRSA endemicity. Identical inactivating agr mutations were not detected in epidemiologically unlinked clones within or between hospitals. Additionally, most agr mutants had single mutations, indicating that they were short lived. Collectively, the results suggest that agr dysfunction is adaptive for survival in the infected host but that it may be counter-adaptive outside infected host tissues.