Cyclophilin A (CypA) is a ubiquitously distributed intracellular protein belonging to the immunophilin family, which is recognized as the cell receptor for the potent immunosuppressive drug cyclosporine A. In the present study, two isoforms of cyclophilin A gene (named as VpCypA1 and VpCypA2) were isolated and characterized from Venerupis philippinarum by RACE approaches. Both VpCypA1 and VpCypA2 possessed all conserved features critical for the fundamental structure and function of CypA, indicating that the two isoforms of cyclophilin A should be new members of CypA family. The expression of VpCypA2 mRNA in haemocytes was significantly up-regulated and the highest expression level was detected at 96 h post-infection with 7.7-fold increase compared with that in the blank group. On the contrary, the relative expression level of VpCypA1 mRNA was down-regulated rapidly at 6 h post-infection and reached 0.4-fold of the control group. They exhibited different expression profile and identical effect of immune modulation, which might suggest the two VpCypA isoforms exert their function in a manner of synergy. These results provide valuable information for further exploring the roles of cyclophilin A in the immune responses of V. philippinarum.