It has previously been demonstrated that baculovirus infection of the Spodoptera frugiperda Sf-9 (Sf-9) and Trichoplusia ni BTI-Tn-5B1-4 (Tn-5B1-4) insect cell lines leads to oxidative stress as measured by protein and membrane lipid oxidation and that this oxidative damage contributes to cell death. As a result of these findings, it was hypothesized that baculovirus infection stimulates superoxide radical (O-2(.-)) synthesis in the mitochondria and that the resulting O-2(.-) accumulation overwhelms the cells' antioxidant defenses. We investigated the ability of manganese superoxide dismutase (MnSOD) expression (which reduces O-2(.-) to H2O2) to overcome the oxidative damage caused by baculovirus infection. It was found that MnSOD expression significantly reduced oxidative damage in baculovirus-infected Tn-5B1-4 cells but had no significant effect on oxidative damage in baculovirus-infected Sf-9 cells. The results are consistent with the hypothesis that O-2(.-) accumulation in the mitochondria is at least partially responsible for the oxidative damage resulting from the baculovirus infection of insect cells.