Inflammation plays a role in trans-10, cis-12 (10,12) conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal related kinase (ERK) and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1ss) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin (PG) pathway involving phospholipase A2, cyclooxygenase-2 (COX-2), and PGF2a. In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species (ROS) associated with cellular stress, and activation of stress-related proteins (i.e., ATF3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Lastly, 10,12 CLA-mediated decrease of peroxisome proliferator activated receptor (PPAR) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of the PPRE, suggesting RSV increases PPAR activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLA-mediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPAR activity.