It is known that TNF- increases the production of reactive oxygen species (ROS) and decreases antioxidant enzymes, resulting in an increase in oxidative stress. IL-10 appears to modulate these effects. Present study investigates the role of p38 and ERK 1/2 MAP kinases in mediating the interplay of TNF-and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis in Sprague Dawley male rats. Isolated adult cardiac myocytes were exposed to TNF-α (10ng/ml), IL-10 (10ng/ml) and IL-10+TNF- (ratio 1) for 4hrs. H₂O₂ (100 µΜ) as a positive control and antioxidant trolox (20 µmol/L) were used to confirm the involvement of oxidative stress. H₂O₂ treatment increased oxidative stress and apoptosis, TNF- mimicked these effects. Exposure to TNF-significantly increased ROS production, caused cell injury, increased the number of apoptotic cells and Bax/Bcl-xl ratio. This change was associated with an increase in phospho p38mapk to total p38mapk ratio and a decrease in phospho ERK 1/2 to total ERK 1/2 ratio. IL-10 treatment by itself had no effect on these parameters, but it prevented above listed changes caused by TNF-. Antioxidant, trolox modulated TNF- induced changes in Bax/Bcl-xl, cell injury and MAP kinases. Pre-exposure of cells to p38mapk inhibitor SB-203580, prevented TNF- induced changes. Inhibition of ERK pathway with PD98059 attenuated protective role of IL-10 against TNF- induced apoptosis. This study provides the evidence in support of the essential role of p38 and ERK 1/2 MAP kinases in the interactive role of TNF- and IL-10 in cardiac myocyte apoptosis.