Tetracycline, clindamycin, and other protein synthesis inhibitors at subinhibitory concentrations significantly increased the expression of the pivotal virulence regulator agr and production of the agr-regulated cytolytic phenol-soluble modulins in the community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300. Our results suggest that such protein synthesis inhibitors may exacerbate the progression of CA-MRSA disease when applied at concentrations that are too low or when treating infections caused by strains resistant to those antibiotics.