Technical Abstract: Enteric septicemia of catfish (ESC) results from infection by Edwardsiella ictaluri, a Gram-negative bacterium that is highly infectious for channel catfish (Ictalurus punctatus). Losses in fingerlings to market size fish account for about 50% of the total disease losses to catfish producers annually. Acquired immunity is cellular more than humoral in catfish surviving ESC or immunized with low numbers of E. ictaluri. Formalin killed bacterial vaccines have not been successful because only humoral responses have been provoked. We produced a rifampicin resistant mutant of E. ictaluri (RE-33) that stimulated cellular immunity and protection against ESC. The humoral antibody response was weak. The RE-33 vaccine appears to be safe and able to provide protection for as long as 6 months. A single immersion exposure of 2 minutes to a low number of E. ictaluri RE-33 vaccine appears to be safe and able to provide protection for as long as 6 months. A single immersion exposure for 2 minutes to a low number of E. ictaluri RE-33 vaccine stimulated strong acquired immunity against many isolates of E. ictaluri. Immunized catfish clear the infection by 14 days. The rifampicin-mutant E. ictaluri survived long enough to induce strong long-lasting acquired immunity against ESC without the need for booster immunization. Ideally, immunization of 10 day old fry will meet the needs of the catfish producers for a vaccine that will provide protection against ESC.