Many pathogenic bacteria have evolved mechanisms for evading host immune systems. One evasion mechanism is manifest by the surface layer (S‐layer), a paracrystalline protein structure composed of S‐layer proteins (SLPs). The S‐layer, possessed by 2 Campylobacter species ( C. fetus and C. rectus ), is external to the bacterial outer membrane and can have multiple functions in immune avoidance. C. fetus is a pathogen of ungulates and immunocompromised humans, in whom it causes disseminated bloodstream disease. In C. fetus , the S‐layer is required for dissemination and is involved in 2 mechanisms of evasion. First, the S‐layer confers resistance to complementmediated killing in non‐immune serum by preventing the binding of complement factor C3b to the C. fetus cell surface. S‐layer expressing C. fetus strains remain susceptible to complementindependent killing, utilizing opsonic antibodies directed against the S‐layer. However, C. fetus has also evolved a mechanism for avoiding antibody‐mediated killing by high‐frequency antigenic variation of SLPs. Antigenic variation is accomplished by complex DNA inversion events involving a family of multiple SLPencoding genes and a single SLP promoter. Inversion events result in the expression of antigenically variant S‐layers, which require distinct antibody responses for killing. C. rectus is implicated in the pathogenesis of periodontal disease and also possesses an S‐layer that appears to be involved in evading the human system. Although studied less extensively than its C. fetus counterpart, the C. rectus S‐layer appears to confer resistance to complement‐mediated killing and to cause the down‐regulation of proinflammatory cytokines. Ann Periodontol 2002;7:43‐53.