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Introduction Rates of sexually transmitted infections are on the rise globally, including those caused by Neisseria gonorrhoeae. Retrospective analyses across clinical settings around the world have indicated that rates of gonorrhoea declined following mass campaigns with vaccines made with outer membrane vesicles (OMV) from N. meningitidis serogroup B, a pathogen closely related to N. gonorrhoeae. The US Food and Drug Administration (FDA)-approved N. meningitidis serogroup B vaccine (4CMenB) contains N. meningitidis OMV and five recombinant protein components: factor H-binding protein (fHbp), Neisserial heparin-binding antigen (NHBA), Neisseria adhesin A (NadA) and the fusion partners genome-derived Neisseria antigen (GNA) 2091 and GNA1030 (used to stabilise fHbp and NHBA, respectively); N. gonorrhoeae encodes homologues of fHbp, NHBA, GNA2091 and GNA1030, but not NadA. Humans and mice immunised with 4CMenB have been shown to develop antibodies directed against N. gonorrhoeae antigens, and 4CMenB immunised mice exhibit enhanced N. gonorrhoeae clearance in a vaginal-infection model versus mock immunised mice. Collectively, these data led to the hypothesis that immunisation with 4CMenB may provide cross-protection against N. gonorrhoeae. There is a unique and time-sensitive opportunity to test the effectiveness of this vaccine in preventing N. gonorrhoeae using the human male urethral challenge model.Methods and analysis This is a double-blind randomised controlled trial testing the efficacy of the FDA-approved 4CMenB vaccine in preventing experimental N. gonorrhoeae infection. Our research team is currently the only in the world to use the established controlled human infection model to study N. gonorrhoeae in its natural human host. Males aged >18 years and <36 years with no medical contraindication to 4CMenB administration, no contraindication to intraurethral challenge with N. gonorrhoeae and who are willing and able to consent and participate in the study will be enrolled in this study. Participants who complete both immunisation and N. gonorrhoeae challenge phases will be included in the primary endpoint analyses of N. gonorrhoeae infection in each study group to determine the efficacy of standard immunisation with 4CMenB in preventing experimental gonococcal infection. The secondary objective is to determine whether 4CMenB vaccinations change or delay the onset of urethritis symptoms.Ethics and dissemination All participants enrolled in the study provided informed consent twice. This study has been reviewed and approved by the University of North Carolina at Chapel Hill Institutional Review Board (#21-0498). Data collection for this study is ongoing.Trial registration number NCT05294588.