Statins belong to a class of drugs well known for their ability to reduce circulating low-density lipoprotein cholesterol. In addition to cholesterol lowering, they also exhibit potential antiinflammatory and antioxidant properties, suggesting that tissues other than liver may be targeted by statins to exert their beneficial metabolic effects. Adipocytes have received very little attention as a potential target of these drugs, possibly because adipocytes are not a major source of biosynthetic cholesterol. Here, we examine the effects of simvastatin on the secretory pathway, inflammation, and cellular metabolism of adipocytes as well as on whole-body insulin sensitivity. We find that statins have a selective effect on the secretion of the insulin-sensitizing adipokine adiponectin by reducing circulating levels of the high-molecular-weight form of adiponectin specifically with a concomitant increase in intracellular adiponectin levels. However, these effects on adiponectin do not translate into changes in metabolism or whole-body insulin sensitivity, potentially due to additional antiinflammatory properties of statins. In addition, ob/ob mice treated with statins have reduced adiposity and an altered ultrastructure of the plasma membrane with respect to caveolar histology. Our data demonstrate that statins have major effects on the cellular physiology of the adipocyte on multiple levels.