OBJECTIVE To investigate effect of cerebellar fastigial nuclei (FN), one of three deep nuclei in cerebellum, on lymphocyte function, and possible central pathway involved in the effect. METHODS Kainic acid (KA) was microinjected into bilateral FN of rats. On the eighth day after the surgery, lymphocytes from the mesenteric lymph nodes were incubated to measure their proliferative reaction to concanavalin A (Con A) by means of colorimetric assay of methyl thiazole tetrazolium (MTT), and natural killer (NK) cells from the spleen were cultured to evaluate their cytotoxicity to YAC-1 cells with the aid of flow cytometric assay. Simultaneously, glutamate content in the hypothalamus was determined by high performance liquid chromatography (HPLC). As control, 0.9% saline was microinjected into the bilateral FN of rats. When these experiments ended, cerebellar sections and Nissl stain for each rat were made to observe the location and extent of the lesions. If the lesion areas were not in the bilateral FN or not limited in the FN, the results were discarded. RESULTS On day 8 following the KA injection of FN, the Nissl-stained cerebellar sections showed the neuronal bodies in the FN were effectively damaged by KA. Simultaneously, the lymphocyte proliferation induced by Con A was significantly increased and the NK cell cytotoxicity to YAC-1 target cells was remarkably enhanced when compared with those of the control animals microinjected with saline in their bilateral FN. At the same time as these changes of lymphocyte functions occurred, glutamate content in the hypothalamus was markedly reduced relative to that in the control hypothalamus. CONCLUSIONS Effective lesions of cerebellar bilateral FN of rats can cause an enhancement of lymphocyte functions, including increase of proliferation of T cells and cytotoxicity of NK cells. The cerebello hypothalamic glutamatergic projections may be involved in the pathway of cerebellar FN immunomodulation.