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Background. Immunogenetic factors predisposing to recurrent genital herpes remain poorly characterized. Methods. In a prospective case-control study, 52 consecutive patients with frequently recurring outbreaks of genital herpes were compared with 80 herpes simplex virus (HSV)-seropositive (types 1 and 2) and 70 HSVseronegative control subjects. Immunoglobulins (Igs), type-specific anti-HSV-2 IgG and IgG subclass antibodies against glycoprotein G, levels of C3 and C4, and classical pathway hemolytic complement activity were measured, and IgG1 and IgG3 allotyping; C4 immunophenotyping; C4* real-time polymerase chain reaction (PCR) genotyping; and HLA-A*, B*, and DR* typing were performed. Results. The G3mg,G1ma/a(x) haplotype was more frequent in patients than in HSV-seronegative control subjects (P = .047). Compared with all control subjects, low levels of total IgG1 (odds ratio [OR], 4.9 [95% confidence interval {CI}, 2.0–12.5]; P = .001) and IgG3 (OR 3.6 [95% CI 1.7–7.8]; P = .001), but not of anti-HSV-2 antibodies, were associated with recurrences. Levels of complement were lowest in patients. The C* null type was negatively associated with neuralgia (OR, 0.2 [95% CI, 0.06–0.81]; ). P =.022). Conclusions. Low levels of antibody-dependent cellular cytotoxicity-mediating IgG1 and IgG3 antibodies, partly dependent of allotype, may predispose to recurrent genital herpes. Antibodies produced by T helper type 1 responses, potentially against an unknown epitope, appear to be relevant in recurrences. In patients, C4* deficiencies are associated with protection from herpetic neuralgias, possibly through reduced inflammation. [ABSTRACT FROM AUTHOR]