The hallmark of gonorrhea is an intense inflammatory response that is characterized by polymorphonuclear leukocytes (PMNs) with intracellular gonococci. A redundancy of defenses may protect Neisseria gonorrhoeae from phagocyte-derived reactive oxygen species. Here we showed that a gonococcal catalase (kat) mutant in strain MS11 was more sensitive to H(2)O(2) than mutants in cytochrome c peroxidase (ccp), methionine sulfoxide reductase (msrA), or the metal-binding protein (mntC) of the MntABC transporter. kat ccp and kat ccp mntC mutants were significantly more sensitive to H(2)O(2) than mutants in any single factor. None of the mutants showed increased susceptibility to murine PMNs. Recovery of the mntC and kat ccp mntC mutants from the lower genital tract of BALB/c mice, but not the kat or kat ccp mutants, was significantly reduced relative to wild-type bacteria. Interestingly, unlike the MS11 kat mutant, a kat mutant of strain FA1090 was attenuated during competitive infection with wild-type FA1090 bacteria. The FA1090 kat mutant and MS11 mntC mutant were also attenuated in mice that are unable to generate a phagocytic respiratory burst. We conclude that inactivation of three well-characterized antioxidant genes (kat, ccp, and mntC) does not increase gonococcal susceptibility to the phagocytic respiratory burst during infection and that gonococcal catalase and the MntC protein confer an unidentified advantage in vivo. In the case of catalase, this advantage is strain specific. Finally, we also showed that an msrA mutant of strain MS11 demonstrated delayed attenuation in BALB/c but not C57BL/6 mice. Therefore, MsrA/B also appears to play a role in infection that is dependent on host genetic background.