There is increasing evidence that leptin affects immune responses and that in the absence of leptin, immunity is suboptimal. Most data so far indicate that leptin increases proinflammatory immune responses by an effect on T cells and macrophages. Here we show that, under certain circumstances, leptin can inhibit T cell proliferative responses. Separation of the responding T cells into different subpopulations revealed an interesting heterogeneity of cellular behavior in that naïve and memory T cells were differentially affected by leptin. The anti-CD3-driven proliferation of memory T cells was inhibited by leptin, whereas that of naïve T cells was markedly enhanced. Despite the inhibition of proliferation of the memory T cells, their production of interferon-gamma was substantially increased. These data show that leptin can inhibit certain immune responses in vitro. However, despite this inhibition of proliferation, the production of proinflammatory cytokines is significantly enhanced by leptin. The findings demonstrated here show further complexity in the actions of leptin on the immune system.