mexCD-oprJis an envelope stress-inducible multidrug efflux operon ofPseudomonas aeruginosa. A gene encoding a homologue of the NfxB repressor of this operon, PA4596, occurs downstream ofoprJand was proposed as a second repressor of this efflux operon. Inactivation of this gene had no impact onmexCD-oprJexpression in cells not exposed to envelope stress although its loss under envelope stress conditions yielded a > 10-fold increase inmexCD-oprJexpression. Consistent with PA4596 functioning as amexCD-oprJrepressor, the purified protein was able to bind to a DNA fragment carrying themexCD-oprJpromoter region. Expression of PA4596 was induced under conditions of envelope stress dependent on the AlgU envelope stress sigma factor, consistent with PA4596 operating under envelope stress conditions where it possibly serves to moderate envelope stress-induciblemexCD-oprJexpression.nfxBmutants showed elevated PA4596 expression and purified NfxB bound to DNA encompassing the PA4596 upstream region, an indication that NfxB functions as a repressor of PA4596 expression. Elimination of PA4596 inP. aeruginosalackingnfxBand hyperexpressingmexCD-oprJhad no additional impact onmexCD-oprJexpression, regardless of the presence of envelope stress, suggesting that PA4596 repressor activity may be dependent on NfxB. This envelope stress-regulated repressor ofmexCD-oprJhas been renamedesrC.