The antidiabetic effects of Lactobacillus casei (LC) on a non-insulin-dependent diabetes mellitus (NIDDM) model, KK-A^y mice, were investigated. The oral administration of LC to male 4-week-old KK- A^y mice, or raising the mice on a 0.05% LC-containing diet significantly decreased the plasma glucose at 8 to 10 weeks of age compared with the control group. The body weights of the LC-treated groups were lower than those of the control group, although the food intake was nearly the same in all groups. Phenotypic analysis of spleen cell surface markers revealed that the increase in CD4⁺ T cells at 12 weeks was significantly inhibited by the oral treatment with LC. Cytokine production, especially that of interferon-γ and interleukin 2, was also inhibited in the oral LC-treated group. The plasma insulin levels of the LC-treated groups were also lower than those of the control group, and the insulin binding potential of red blood cells in the LC-treated mice was augmented more than that in the control group. Taken together, these findings led us to conclude that the oral administration of LC in the NIDDM model mice, KK-A^y, was involved in the decrease in the plasma glucose level and modified the host immune responses.