We investigated the role of chromosomal beta-lactamase and the MexAB-OprM efflux system in intrinsic resistance to beta-lactams in Pseudomonas aeruginosa. Determination of the susceptibilities of a series of isogenic mutants with impaired production of the beta-lactamase and the efflux system to 16 beta-lactams including penicillins, cephems, oxacephems, carbapenems, and a monobactam demonstrated that the intrinsic resistance of P. aeruginosa to most of the beta-lactams is due to the interplay of both factors.