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CD59 is a complement regulatory protein that inhibits the formation of membrane attack complex of complement. In this study, we examined the expression and activity of tongue sole (Cynoglossus semilaevis) CD59 (CsCD59). CsCD59 possesses the conserved structural features of CD59 and shares 33%–46% sequence identities with other fish CD59. Expression of CsCD59 was high in liver, spleen, and muscle, and was stimulated by infection of bacterial pathogens. Recombinant CsCD59 (rCsCD59) exhibited an apparent inhibition effect on the activation of tongue sole serum complement. ELISA and microscopy detected binding of rCsCD59 to a number of Gram-negative and Gram-positive bacteria. Interaction with rCsCD59 did not affect bacterial viability but significantly enhanced bacterial resistance against the killing effect of fish serum. Together these results indicate that fish CD59 may to some degrees facilitate a general escape of bacteria from complement-mediated immunity.CsCD59 shares 33%–46% overall sequence identities with known fish CD59.CsCD59 expression was detected in nine tissues and enhanced by bacterial infection.rCsCD59 inhibited complement-mediated hemolysis of rabbit red blood cells.rCsCD59 bound to different bacteria but had no effect on bacterial viability.Pre-binding of rCsCD59 to bacteria enhanced bacterial survival in fish serum.