Dysfunctional cross-talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (ROSI) improves insulin resistance yet causes increased adipose mass and weight gain in mice and humans. Conjugated linoleic acid (CLA) reduces adipose mass and body weight gain but induces hepatic steatosis in mice. We examined the combined effects of ROSI and CLA on adiposity, insulin sensitivity and hepatic steatosis in male C57Bl/6 mice fed high fat diet. CLA suppressed weight gain and adipose mass but caused hepatic steatosis. Addition of ROSI attenuated CLA-induced insulin resistance and dysregulation of adipocytokines. In adipose, CLA significantly suppressed lipoprotein lipase, fatty acid translocase FAT/CD36 mRNA and addition of ROSI completely rescued this effect. CLA increased markers of macrophage infiltration F4/80 and CD68 mRNA levels without inducing tumor necrosis factor alpha (TNF) in epididymal adipose tissue. The ratio of Bax/Bcl2 was significantly increased in adipose of CLA group, and was partially prevented by co-treatment with ROSI. In the liver, CLA increased microsteatosis and surprisingly increased the rate of very low density lipoprotein-TG production without inducing TNF and markers of macrophage infiltration. These changes were accompanied by significantly increased mRNA levels of stearoyl-CoA desaturase, FAT/CD36 and fatty acid synthase. The combined administration of CLA and ROSI (CLA/ROSI) reduced hepatic liver triglyceride content as well as lipogenic gene expression when compared to CLA alone.