Oxidative stress and protein glycation can contribute to the development of insulin resistance and complications associated with type 2 diabetes mellitus. The antioxidant α-lipoic acid (ALA) reduces oxidative stress and the formation of advanced glycation end products (AGEs) and improves insulin sensitivity in skeletal muscle and liver. The AGE inhibitor pyridoxamine (PM) prevents irreversible protein glycation, thereby reducing various diabetic complications. The potential interactive effects of ALA and PM in the treatment of whole-body and skeletal muscle insulin resistance have not been investigated. Therefore, this study was designed to determine the effects of combined ALA and PM treatments on reducing muscle oxidative stress and ameliorating insulin resistance in prediabetic obese Zucker rats. Obese Zucker rats were assigned to either a control group or to a treatment group receiving daily injections of the R-(+)-enantiomer of ALA (R-ALA, 92 mg/kg) or PM (60 mg/kg), individually or in combination, for 6 weeks. The individual and combined treatments with R-ALA and PM were effective in significantly (P < .05) reducing plantaris muscle protein carbonyls (33%-40%) and urine-conjugated dienes (22%-38%), markers of oxidative stress. The R-ALA and PM in combination resulted in the largest reductions of fasting plasma glucose (23%), insulin (16%), and free fatty acids (24%) and of muscle triglycerides (45%) compared with alterations elicited by individual treatment with R-ALA or PM. Moreover, the combination of R-ALA and PM elicited the greatest enhancement of whole-body insulin sensitivity both in the fasted state and during an oral glucose tolerance test. Finally, combined R-ALA/PM treatments maintained the 44% enhancement of in vitro insulin-mediated glucose transport activity in soleus muscle of obese Zucker rats treated with R-ALA alone. Collectively, these results document a beneficial interaction of the antioxidant R-ALA and the AGE inhibitor PM in the treatment of whole-body and skeletal muscle insulin resistance in obese Zucker rats.