It is well known that total parenteral nutrition (TPN) causes atrophy of the intestinal mucosa, resulting in degeneration and atrophy of the gut-associated lymphoid tissues (GALT). This study was conducted to examine the suppressive effect of TPN on GALT in rats. Rats that received TPN alone for 2 weeks, i.e., the TPN group, showed a decreased number of Peyer's patches and thoracic duct lymphocytes (TDL), as well as atrophy. Conversely, those treated with TPN in combination with polysaccharide K (PSK) at a daily dose of 1000 mg/kg for 2 weeks, i.e., the PSK group, showed increases in the number of Peyer's patches and TDL and improvement in the TDL subsets compared with the TPN group. Immunohistological examination of the changes in immunocytes in GALT using monoclonal antibodies revealed increases in the production of the major histocompatibility complex (MHC)-I and (MHC)-II, helper T cells, and interleukin 2 (IL-2). These findings indicate that PSK improves GALT suppression induced by TPN.