This study was undertaken to determine whether cyclic AMP (cAMP) or cAMP-receptor protein (CRP) modulates the activity of the autoinducer (AI)-2-mediated quorum sensing (QS) system in response to glucose availability in Vibrio vulnificus. A mutation in crp impaired V. vulnificus growth, decreased AI-2 production, and repressed the expression of smcR encoding the master regulator SmcR (a Vibrio harveyi LuxR homolog) of the AI-2-QS system, and these changes were prevented by in trans complementation of wild-type crp. Furthermore, glucose repressed smcR expression in the presence of CRP but not in its absence. A mutation in cyaA encoding adenylate cyclase, which is required for cAMP synthesis, also impaired V. vulnificus growth and repressed smcR expression, and these changes were recovered by in trans complementation of wild-type cyaA. These results indicate that cAMP or CRP modulates the AI-2-QS system in response to glucose availability in V. vulnificus, demonstrating the presence of a connection between catabolite repression and quorum sensing in V. vulnificus.