Glutaredoxin (abbreviated as Grx) is an important ubiquitous disulfide reductase, which can protect organisms against oxidative stresses. In the present study, a monothiol glutaredoxin gene (named as VpGrx1) and a dithiol glutaredoxin gene (named as VpGrx2) were identified from Venerupis philippinarum. Similar to most Grx2s, VpGrx2 possessed the conserved catalytic residues (C–P–Y–C) and other conserved features critical for the fundamental structure and function of Grx2s, while the active motif (C–G–Y–S) of VpGrx1 was different from the counterpart in other Grx1s. Quantitative Real-time PCR assay showed that VpGrx1 and VpGrx2 transcripts were detected in a wide range of tissues and mainly distributed in gills and hepatopancreas. After Vibrio challenge, both the expression levels of VpGrx1 and VpGrx2 mRNA in hemocytes were significantly up-regulated at 24 h. As concerned to benzo[a]pyrene (BaP) exposure, the expression levels of VpGrx1 and VpGrx2 transcripts in hepatopancreas were also significantly induced at 24 h. These results suggested that ROS could be induced through the respiratory burst to clear the invading bacteria and pollutants. VpGrx1 and VpGrx2 perhaps involved in the regulation of redox homeostasis and innate immune responses of V. philippinarum.