The effects of enteric administration of different preparations of Chlamydia trachomatis prior to ocular challenge with live chlamydia were compared to the immunity that develops after recovery from ocular infection. Oral immunization with either live homologous serovar B or with formalin-killed heterologus serovar L2 did not influence the response to subsequent ocular challenge. Although oral immunization with live serovar led to protection against heterologous ocular challenge with serovar B, oral immunization with noninfectious UV-irradiated serovar L2 led to more severe and prolonged disease. An immunizing regimen designed for maximal mucosal and systemic immunity also resulted in protection against homologous ocular challenge. Although protection was correlated with the presence of serum IgA antibodies, no clear mechanism for the protective ocular immunity to chlamydial infection has emerged. These studies show that it is possible to stimulate mucosal immunity to induce protection against subsequent ocular challenge with C. trachomatis that is equal to that which follows prior ocular infection.