Abstract Serum from rainbow trout Oncorhynchus mykiss (formerly Salmo gairdnert) protected rainbow trout red blood cells (RBCs) from lysis by the hemolysins of Aeromonas salmonicida and Aeromonas hydrophila. Serum also protected RBCs from nonenzymatic lysis by the nonionic detergent NonIdet P40. Sera from other salmonid species and cabezon Scorpaenichthys marmoratus were also protective; sera from channel catfish Ictalurus punctatus, largemouth bass Micropterus salmoides, and newt Taricha granulosa were less protective; and sera from higher vertebrates (chicken, sheep, cow, and horse) were not protective. Cell-free exudate collected from lesions of coho salmon Oncorhynchus kisutch artificially infected with A. salmonicida also inhibited RBC lysis by hemolysin in vitro. The inhibitory factor was not sensitive to selected proteases, was not removed by centrifugation at 100,000 × gravity, and was sensitive to incubation at 60°C or higher for 30 min. Preparative isoelectric focusing and chromatography on Seph...