Chronic obstructive pulmonary disease is associated with systemic effects including reduced body weight, oxidative stress and altered circulating TNFalpha levels. The present study was aimed to investigate whether chronic exposure to cigarette smoke induces these systemic changes in a guinea pig model. Seven animals/group were exposed to the smoke of seven cigarettes/day, 5 days/week, during 2, 4 and 6 months (chronic exposure). Three animals/group were sacrificed immediately, 3 h or 24 h after exposure to seven cigarettes (acute exposure). Chronically smoke-exposed animals exhibited lower body weight gain, starting at 5th week, and goblet cell metaplasia in small bronchioles. At 6 months there was a trend for increased plasma and lung tissue TNFalpha levels. No changes, neither in skeletal muscle glutathione (GSH) nor in plasma lipid peroxidation, were observed at any time point after chronic exposure. However, skeletal muscle GSH decreased and plasma lipid peroxidation increased immediately after acute smoke exposure, equaling control levels thereafter. We conclude that cigarette smoke exposure in the guinea pig induces a transient and repeated oxidative effect, which might result in impaired systemic metabolism and consequent failure of smoke-exposed animals to gain weight. The effects of cigarette smoke on body weight antecede and appear to be independent from the alterations produced in small airways.