Superoxide dismutase (SOD) ubiquitously found in both prokaryotes and eukaryotes functions as the first and essential enzyme in the antioxidant system. In the present study, a manganese SOD (designated as CfmtMnSOD) was cloned from Zhikong scallop Chlamys farreri. The complete cDNA sequence of CfmtMnSOD contained a 681 bp open reading frame (ORF), encoding a peptide of 226 amino acids. A SOD_Fe_N domain and a SOD_Fe_C domain were found in the deduced amino acid sequence of CfmtMnSOD. The mRNA transcripts of CfmtMnSOD were constitutively expressed in all the tested tissues, including gill, gonad, hepatopancreas, hemocytes, mantle and muscle, with the highest expression level in hemocytes. After the stimulation of Vibrio splendidus, Staphylococcus aureus and Yarrowia lipolytica, the mRNA transcripts of CfmtMnSOD in hemocytes all significantly increased. The purified rCfmtMnSOD protein exhibited Mn2+ dependent specific and low stable enzymatic activities. After Vibrio challenge, the cumulative mortality of CfmtMnSOD-suppressed scallops was significantly higher than those of control groups and the semi-lethal time for CfmtMnSOD-suppressed scallops was rather shorter than those of control groups either. Moreover, the final mortality rate of CfmtMnSOD-suppressed group was significant higher than those of control groups, even without Vibrio challenge. All these results indicated that CfmtMnSOD was efficient antioxidant enzyme involved in the innate immunity, and also essential for the survival of C. farreri.