We propose that diabetic foot ulcers and diabetic mouse wounds have insufficient glutathione to maintain correct cellular redox potential. Therefore, tissue samples from the wound edge of diabetic foot ulcers, diabetic mice wounds and nondiabetic mice wounds were obtained. Levels of glutathione, cysteine, and mixed protein disulfide were determined and topical application of esterified glutathione in carboxymethylcellulose or carboxymethylcellulose alone was applied to the mice wounds. Diabetic foot ulcer mean glutathione levels were 150.6 pmol/mg in the controls and 53.4 pmol/mg at the wound edge (p < 0.05), while mean cysteine levels were 22.3 pmol/mg in the control and 10.5 pmol/mg at the wound edge (p < 0.05). The mixed protein disulfide levels were elevated in the wounds (14.6 pmol/mg), but not in the control (6.9 pmol/mg) (p < 0.05). The glutathione levels were lower in the diabetic mouse wounds (155 pmol/mg) than the nondiabetic mouse wounds (205 pmol/mg) (p=0.04). The diabetic mouse treated with carboxymethylcellulose alone healed slower (19.5 +/- 2.2 days) than the nondiabetic mouse DM (11.5 +/- 0.5 days) (p < 0.001). The diabetic mouse that received topical glutathione healed significantly faster (12.5 +/- 0.8 days) than the carboxymethylcellulose-treated mice (19.5 +/- 2.2 days) (p < 0.001). Glutathione levels in the diabetic mouse (26.0 pmol/mg) were lower than in the nondiabetic mouse (311.7 pmol/mg) (p < 0.05) after glutathione treatment. In the glutathione-treated diabetic mouse, the oxidized glutathione was higher (26.7%) than in the nondiabetic mouse (9.9%) (p=0.05). These data suggest that cellular redox dysfunction and lower glutathione levels are present in diabetic foot ulcers and diabetic mouse wounds.