Isomers of conjugated linoleic acid (CLA) are found in beef, lamb and dairy products. Diets containing CLA reduce adipose mass in various depots of experimental animals. In addition, CLA delays the onset of diabetes in the ZDF rat model for obesity-linked type 2 diabetes mellitus. We hypothesize that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes mellitus. In this double-blind study, subjects with type 2 diabetes mellitus were randomized into one of two groups receiving either a supplement containing mixed CLA isomers (CLA-mix; 8.0 g daily, 76% pure CLA; n = 12) or a supplement containing safflower oil (placebo; 8.0 g daily safflower oil, n = 9) for 8 wk. The isomers of CLA in the CLA-mix supplement were primarily c9t11-CLA ( approximately 37%) and t10c12-CLA ( approximately 39%) in free fatty acid form. Plasma levels of CLA were inversely associated with body weight (P < 0.05) and serum leptin levels (P < 0.05). When levels of plasma t10c12-CLA isomer were correlated with changes in body weight or serum leptin, t10c12-CLA, but not c9t11-CLA, was inversely associated with body weights (P < 0.05) and serum leptin (P < 0.02). These findings strongly suggest that the t10c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in subjects with type 2 diabetes. Future studies are needed to determine a causal relationship, if any, of t10c12-CLA or c9t11-CLA to modulate body weight and composition in subjects with type 2 diabetes. Furthermore, determining the ability of CLA isomers to influence glucose and lipid metabolism as well as markers of insulin sensitivity is imperative to understanding the role of CLA to aid in the management of type 2 diabetes and other related conditions of insulin resistance.