A phosvitin (Pv)-derived peptide, Pt5, which consists of the C-terminal 55 residues of Pv in zebrafish, has been shown to function as an antimicrobial agent capable of killing microbes in vitro. However, its in vivo role in zebrafish remains unknown. In this study, we clearly demonstrated that Pt5 protected adult zebrafish from pathogenic Aeromonas hydrophila attack, capable of significantly enhancing the survival rate of zebrafish after the pathogenic challenge. Pt5 also caused a marked decrease in the numbers of A. hydrophila in the blood, spleen, kidney, liver and muscle, suggesting that Pt5 was able to block multiplication/dissemination of A. hydrophila in zebrafish. Additionally. Pt5 markedly suppressed the expression of the proinflammatory cytokine genes IL-1 beta, IL-6, TNF-alpha and IFN-gamma in the spleen and head kidney of A. hydrophila-infected zebrafish, but it considerably enhanced the expressions of the antiinflammatory cytokine genes IL-10 and IL-4 in the same tissues. Taken together, these data indicate that Pt5 plays a dual role in zebrafish as an antimicrobial and immunomodulatory agent, capable of protecting zebrafish against pathogenic A. hydrophila through its antimicrobial activity as well as preventing zebrafish from the detrimental effects of an excessive inflammatory response via modulating immune functions. (C) 2012 Elsevier Inc. All rights reserved.