We previously reported that the cerebellar fastigial nucleus, output nucleus of the spinocerebellum, modulates lymphocyte function. To further explore the role of the cerebellum in neuroimmunomodulation, we here lesioned bilaterally the cerebellar interposed nuclei (IN) of rats with kainic acid (KA) injections. On days 8, 16 and 32 after IN lesions, lymphocyte percentage in peripheral white blood cells was examined. Furthermore, proliferation of lymphocytes from mesenteric lymph nodes induced by concanavalin A, sheep red blood cell-specific IgM antibody in the serum and cytotoxicity of natural killer cells from spleen against YAC-1 cells were measured by methyl-thiazole-tetrazolium assay, enzyme-linked immunosorbent assay and flow cytometric assay, respectively. On days 8, 16 and 32 after KA injection in the IN, the lymphocyte percentage in the peripheral white blood cells was notably diminished with respect to control rats injected with saline in the IN. Concanavalin A-induced lymphocyte proliferation, serum sheep red blood cell-specific IgM antibody and natural killer cell toxicity of the IN-lesioned rats were significantly attenuated with respect to IN-saline control rats at all the post-lesion time points. The findings reveal that KA-induced neuronal loss in the IN of both sides exerts an inhibitory effect on number and functions of T, B and natural killer lymphocytes, and indicate that the cerebellar IN participates in regulating immune function. Thus, the data suggest that the cerebellum may be an important brain area for neuroimmunomodulation, besides its well-known role in motor control.