Background: Animal studies have demonstrated intestinal immunoglobulin production is decreased when luminal nutrition is withheld and nutrition is provided solely on the basis of total parenteral nutrition (TPN). Methods: Eight normal volunteers were hospitalized in the Clinical Research Center for three weeks. The subjects received TPN as an exclusive means of nutritional support for 14 days followed by 5 days of enteral feeding with either standard or a glutamine- and arginine-supplemented formula in which the protein source was primarily free amino acids and peptides. Endoscopic jejunal biopsies obtained before and after TPN and following enteral refeeding were evaluated by immunofluorescence for the number of IgA, IgM and IgG- producing cells; T and B cells as well as intraepithelial and lamina propria lymphocytes were also counted. Serum immunoglobulins and the molecular forms of serum IgA were determined at the same intervals. Results: The number of intestinal IgA-, IgM- and IgG-producing cells was unaffected by TPN (676 ± 58 vs. 643 ± 38, 101 ± 14 vs. 98 ± 18, 10 ± 1 vs. 11 ± 2 per low power field). The total number of intestinal lymphocytes, and CD3+ lymphocytes in the intraepithelial area was unaffected by TPN (10.4 ± 0.4 vs. 10.2 ± 1.3, 7.3 ± 0.8 vs. 8.6 ± 1.6 per 100 epithelial cells). Similarly, the total number of lymphocytes and CD3+ lymphocytes in the intestinal lamina propria was unaffected by TPN (4.4 ± 0.2 vs. 6.2 ± 0.8, 3.3 ± 0.7 vs. 4.5 ± 0.8). A small, but statistically significant increase in serum IgA and IgM was seen with TPN 314 ± 11 vs. 342 ± 16 mg/dL and 154 ± 25 vs. 226 ± 47 mg/dL, although IgG remained unchanged (1262 ± 69 vs. 1207 ± 57 mg/dL). The proportion of polymeric and monomeric serum IgA remained unchanged after TPN (19.2 vs. 22.1% polymeric). Conclusion: The use of TPN is not associated with intestinal immune dysfunction in man. A small, but statistically significant increase in serum IgM, and a borderline statistically significant increase in serum IgM were associated with TPN. The etiology and clinical significance of these observations is unclear. © 1995 American College of Nutrition.