The relationship between body condition score (BCS) with measures of oxidative status and TNF-alpha production was examined in 16 mid-lactation dairy cows. Cows were selected based on either a normal (2.5-2.7) or a high (> or =3.5) BCS using the standard five-point scaling system. The metabolic status of all cows was determined by plasma nonesterified fatty acid levels (NEFA). Plasma samples or white blood cell lysates also were analyzed for indices of oxidant stress and for the expression of TNF-alpha. Cows with a high BCS had significantly lower NEFA levels when compared to normal BCS cows and the over-conditioned animals were not in a state of negative energy balance. No significant changes in lipid hydroperoxide levels, glutathione peroxidase activity, or the ratio of reduced (GSH) to oxidized (GSSG) glutathione was detected with respect to BCS. However, high BCS cows did have a significantly lower overall antioxidant potential and reduced TrxR activities when compared with the normal BCS cows. Changes in the oxidative state of over-conditioned cows were accompanied by a significantly higher expression of TNF-alpha. Results from this study suggest that cows with a high BCS can experience oxidant stress in the absence of altered energy status. Increased TNF-alpha expression may be related to the pro-oxidant state of over-conditioned cows and possibly be a contributing factor to the enhanced susceptibility to disease in high BCS dairy cattle.