Since several lines of evidence point to high-fat diet-induced obesity accompanied with chronic low-grade inflammation, we hypothesized that immune modulators could prevent the development of high-fat diet-induced obesity. To address this issue, we selected three commonly used immune modulators: cyclosporine A, fingolimod and laquinimod to explore their roles in preventing of high-fat diet-induced obesity by twice weekly i.p. injection. Our results showed that cyclosporine A, fingolimod and laquinimod treatment protected the mice from development of insulin resistance and maintained glucose sensitivity with a high-fat diet. Also, real-time PCR analysis demonstrated that the expression levels of inflammatory related genes were down-regulated on fingolimodand laquinimod treatment mice. These beneficial effects were associated with blockade of macrophage infiltration and suppression of immune responses. Therefore, cyclosporine A, fingolimod and laquinimod may be the potential therapies in preventing of high-fat diet-induced obesity.