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The alternative complement pathway (ACP) provides the non-immune channel catfish ( Ictalurus punctatus ) with protection against many Gram-negative bacteria. Very little serum bactericidal activity (0–13%) was found against 8 fish pathogens, but a strong bactericidal response (100%) was found against 7 non-pathogens. MgEGTA chelation of catfish serum did not essentially change the bactericidal results. Catfish serum heated at 56°C and serum adsorbed with zymosan had no bactericidal activity. This demonstrated that the ACP was responsible for the bactericidal response. The molecular nature of the microbial surface determines whether or not the ACP will be activated. A relative lack of surface sialic acid has been found to be important for binding complement Factor B of the ACP by susceptible microbial surfaces. This study therefore examined the 15 Gram-negative bacterial fish pathogens and non-pathogens by determining their sialic acid content and their ability to elicit a bactericidal response by the catfish ACP. It was found that there was very little bactericidal activity against the fish pathogens that contained sialic acid but a very strong bactericidal response (100%) against the non-pathogens that lacked sialic acid (p=.0043). A relative lack of sialic acid or no sialic acid therefore correlated with a strong bactericidal response by the catfish ACP. Neuraminidase treatment of the bacterial fish pathogens to remove sialic acid greatly increased the bactericidal response against them by the catfish ACP when compared with untreated bacteria (p=.0431).