During human infection, Neisseria gonorrhoeae colonizes mucosal sites, an environment that is enriched in host-derived antimicrobials, including the cell wall-degrading enzyme lysozyme. N. gonorrhoeae has developed strategies to counteract lysozyme activity, including maintenance of envelope integrity, peptidoglycan modifications and protein inhibitors of lysozyme. Ragland et al. show that Ng_1063 and a previously described protein, Ng_1981, contribute to full resistance of N. gonorrhoeae against lysozyme. Lysozyme interacts with Ng_1063 and Ng_1981, and treatment of N. gonorrhoeae with lysozyme increased their protein levels. Both proteins exhibit similar ability to inhibit the lytic activity of lysozyme and were crucial for cell survival in the presence of lysozyme. Finally, Ng_1981 is both released extracellularly and located in the bacterial envelope, whereas Ng_1063 is anchored to the outer membrane and surface-exposed.