Calcineurin (CN) is known to be involved in many biological processes, particularly, the immune response mechanism in many invertebrates. In this study, we characterized both HcCNA and HcCNB genes in Haliotis diversicolor, documented their expression in many tissues, and discerned their function as immune responsive genes against Vibrio parahaemolyticus infection. Similar to other mollusk CNs, the HcCNA gene lacked a proline-rich domain and comprised only one isoform of its catalytic unit, in contrast to CNs found in mammals. HcCNB was highly conserved in both sequence and domain architecture. Quantitative PCR and in situ hybridization revealed that the genes were broadly expressed and were not restricted to tissues traditionally associated with immune function. Upon infection of H. diversicolor with V. parahaemolyticus (a bacteria that causes serious disease in crustaceans and mollusks), both HcCNA and HcCNB genes were highly up-regulated at the early phase of bacterial infection. HcCNB was expressed significantly higher than HcCNA in response to bacterial challenge, suggesting its independent or more rapid response to bacterial infection. Together, the two CN genes are unique in their gene structure (particular HcCNA) and distribution in mollusk species and likely function as immune responsive genes along with many other genes that are enhanced in the early phase of V. parahaemolyticus infection in abalone.