Technical Abstract: Differences in mortality, growth, and immune response among genetic groups of catfish exposed to virulent Edwardsiella ictaluri. Survivorship to ESC varies among and within strains of commercially raised catfish, however the immunological basis for differences in susceptibility is not well-understood. We measured mortality, pathogen levels (bacterial DNA), specific growth rate (SGR), toll-like receptor (TLR3 and TLR5) mRNA expression, and lysozyme activity during experimental challenge with virulent Edwardsiella ictaluri in three strains of channel catfish: USDA103 (103), Red River (RR), USDA103 x Red River, and blue catfish, as well as USDA103 x blue hybrids. Fish were sampled during a 21 day pathogen challenge. Blue catfish were the least susceptible (24% mortality) and had the lowest mean pathogen loads (3.4x102 ± 9.3x101 cell-equiv/mg). In contrast, 103 catfish were the most susceptible (65% mortality) and had the highest mean pathogen loads (1.1x104 ± 6.4x103 cell-equiv/mg). The most susceptible genetic groups (103, 103 x RR, and RR) had reduced SGR during the 21 d challenge. Differences in lysozyme activity paralleled mortality rates. USDA103 had the highest (67.3±28.7 U/mL) and Blue the lowest (13.2±3.2 U/mL) mean lysozyme activity. In kidney, expression of TLR3 mRNA differed between strains early and late in challenge. TLR5 mRNA differences were evident among strains throughout challenge with significant downregulation occurring in all strains on day 1 and 4. In spleen, all strains had elevated levels of TLR3 and TLR5 mRNA 1d post-exposure. In stomach, only one strain (103 x RR) showed upregulation throughout challenge. The relationship of phenotypic (mortality and growth) and immune responses measured here suggest that variation in susceptibility to ESC is a function of differences in innate immune response. Understanding these differences will be crucial for enhancing the immune system through selective breeding and in developing disease management protocols for channel catfish.