Thiazolidinediones (TZDs) are potent insulin-sensitizing compounds and high-affinity ligands for the transcription factor peroxisomal proliferator-activated receptor γ. The mechanism through which TZDs improve insulin sensitivity, however, is not clear. In this study, we asked whether the ability of TZD to suppress and antagonize TNFα is an underlying mechanism for its molecular and physiological effects, using obese (ob/ob) mice lacking TNFα function. We found that the lipid-lowering effects of TZD are completely independent of TNFα suppression, and the insulin-sensitizing effects of TZD are partially independent. TZD treatment improved insulin sensitivity in ob/ob mice both with and without functional TNFα, albeit with different absolute potency. To characterize the potential interdependency of TZD- and TNFα-regulated pathways at the molecular level, we also performed four-way transcriptional profiling of white adipose tissue of TZD- and vehicle-treated ob/ob mice, with and without TNFα function. The majority of metabolic genes identified were regulated independent of the presence of TNFα, whereas most effects on inflammatory mediators were dependent on TNFα. This study demonstrates that the insulin-sensitizing action of TZD occurs partially through TNF-independent mechanisms, although a subset of the molecular effects of TZD treatment in adipose tissue depends on TNFα.