BACKGROUND: Understanding host factors modulating immunity to Neisseria gonorrhoeae infection may benefit work on vaccine development. METHODS: We analyzed longitudinal data collected from 485 male and female adolescents to determine genetic correlates of genital gonorrhea. Cytokine data from 388 females were analyzed to assess immunologic markers of gonorrhea and their relationship to genetic correlates. RESULTS: The T-G haplotype defining interleukin-2 (IL-2) gene promoter and intron 1 polymorphisms (-330T and -166G) was more frequently found in individuals who had gonorrhea (relative odds = 3.2, P = 0.01). Among 3 endocervical cytokines measured, IL-10 and IL-12 concentrations were higher and IL-2 lower when gonorrhea was detected. The decrease in endocervical IL-2 after gonorrhea acquisition was mostly restricted to subjects with the IL2 T-G haplotype, which may reflect involvement of a pathogen-specific and genetically mediated mechanism for differential IL-2 responses at genital mucosa. In addition, 2 human leukocyte antigen variants (Cw*04 and DQB1*05) were also independently associated with gonorrhea (adjusted relative odds = 1.9 and 0.5, respectively; P <0.05 for both). CONCLUSIONS: Confirmation of immunogenetic correlates of gonorrhea in larger cohorts may be useful in guiding further research on both innate and adaptive immune responses to N. gonorrhoeae. © 2008, American Sexually Transmitted Diseases Association.