Manganese superoxide dismutase (MnSOD) protects mitochondria from oxidative damage. Alterations in the regulation of MnSOD plays an important role in the development of many types of cancer. Activity of this enzyme is induced by inflammatory cytokines and other conditions that increase oxygen radical production. High levels of dietary lipid have been shown to decrease MnSOD activity. This study was designed to define the effect of various type of fatty acids on MnSOD activity and MnSOD induction. IEC-6 cells were treated with 40 micromol/l of either linoleic acid (LA), eicosapentaenoic acid (EPA), or oleic acid (OA) in the presence or absence of 10 ng/ml tumor necrosis factor-alpha (TNF-alpha). Fatty acid supplementation increased MnSOD activity. MnSOD activity was greater in the LA group than in the EPA or OA groups. TNF-alpha induced MnSOD activity equally in all fatty acid-supplemented groups. High levels of MnSOD activity may be an indicator of chronic inflammation resulting from fatty acid, particularly LA, supplementation.