Technical Abstract: Protective immunity against enteric septicemia of catfish (ESC) following immunization with Edwardsiella ictaluri bacterins and controlled live exposure to E. ictaluri was investigated. Mean cumulative percent survival was significantly higher (P < 0.05) in controlled live vaccinates (100.0%) than in immersion and oral bacterin vaccinates (68.3 and 50.0%, respectively). In two other experiments using bacterin immersion, survival patterns were similar between vaccinates (37.1 and 47.8%) and non-vaccinates (57.8 and 56.7%). The bactericidal activity against E. ictaluri by peritoneal macrophages from controlled live vaccinates (85.9%) was significantly greater (P_< 0.05) than bactericidal activity of macrophages from immersion bacterin vaccinates (71.4%) or non-vaccinates (68.1%). No significant (P > 0.05) difference was found in the bactericidal activity of macrophages from oral bacterin vaccinates and macrophages from controlled live vaccinates. The E. ictaluri specific antibody response of controlled live (0.08 OD) and immersion bacterin vaccinates (0.11 OD) was significantly higher (P < 0.05) than that of oral bacterin vaccinates and non-vaccinates (0.01 OD) 15 days post vaccination. A significantly higher antibody response was seen in controlled live vaccinates (0.17 OD), when compared to other vaccinates or non-vaccinates 33 days after vaccination. All treatment groups produced antibodies specific to E. ictaluri exoantigen after challenge with E. ictaluri. Either immersion or oral bacterins did not protect vaccinates against ESC. Controlled live E. ictaluri immunization of channel catfish resulted in production of specific antibodies, increased macrophage bactericidal activity and protection against ESC.