Combined antioxidant deficiencies of selenium and vitamin E or vitamin E and vitamin C in guinea pigs result in clinical illness. We hypothesized that combined selenium and vitamin C deficiency would have clinical consequences because in vitro interactions of these antioxidant nutrients have been reported. Since guinea pigs are dependent on dietary vitamin C, weanling male guinea pigs were fed selenium-deficient or control diet for 15 weeks prior to imposing vitamin C deficiency. Four dietary groups were formed and studied 3 weeks later: controls, vitamin C deficient, selenium deficient, and doubly deficient. Deficiencies were confirmed by determinations of glutathione peroxidase activity and vitamin C concentration in liver and skeletal muscle. Plasma creatine phosphokinase (CPK) activity and liver, kidney, heart, and quadriceps histopathology were determined. Doubly deficient animals had moderately severe skeletal muscle cell death as judged by histopathology and plasma CPK activity of 6630 ± 4400 IU/L (control 70 ± 5; vitamin C deficient 95 ± 110; selenium deficient 280 ± 250). Liver, kidney, and heart histology was normal in all groups. Muscle α-tocopherol levels were not depressed in the doubly deficient group but muscle F 2 isoprostane concentrations were elevated in them and correlated with markers of cell death. We conclude that combining selenium and vitamin C deficiencies in the guinea pig causes cell death in skeletal muscle that is more severe than the injury caused by selenium deficiency. The elevation of muscle F 2 isoprostanes is compatible with the cell death being caused by oxidative stress.