Patients with long-standing diabetes may have a propensity for infection-related mortality. In this study, lymphocyte subsets, the proliferative response of splenocytes to mitogens, and circulating levels of tumor necrosis factor alpha (TNF-α) in genetically obese-diabetic Wistar fatty (fa/fa) rats (WF) were longitudinally compared versus lean (+/?) litters (WL). Moreover, the effects of weight reduction with voglibose treatment on immunity were evaluated (WFV and WLV). Body weight was significantly increased in WF compared with WL. Hyperglycemia and hyperlipidemia developed, respectively, 11 weeks and 5 weeks thereafter throughout the observation periods. Circulating T cells and T-cell subsets of WF were significantly reduced after 22 weeks. There were also significant decreases in CD4⁺ and CD8⁺ thymocytes and the proliferative response of splenocytes. Circulating levels of TNF-α were significantly increased in WF. Treatment with voglibose resulted in significantly reduced blood glucose, insulin, cholesterol, triglyceride, and body weight in WFV. After weight reduction, circulating T cells and T-cell subsets were increased and TNF-α was decreased significantly in WFV. Our results suggest that the number and function of T cells in WF may be reduced, which may be related at least in part to elevated TNF-α levels, although the role of the other factors such as glucose, insulin, cholesterol, and triglycerides on T-cell immunity should be further investigated.