Nucleotide (NT) nitrogen, a component of nonprotein nitrogen, accounts for approximately 0.1% to 0.15% of the total nitrogen content of human milk. The results of studies in animals indicate that dietary NTs may be required for maintenance of normal immune function. Thirty-seven healthy term infants were either breast-fed (n = 9) or fed SMA formula supplemented with 33 mg of NTs per liter (n = 13, NT+) or standard SMA formula (n = 15; NT-). At 2 months of age, natural killer cell percent cytotoxicity was significantly higher in the breast-fed and NT+ groups compared with the NT- group (41.7 +/- 4.7, 32.2 +/- 3.4, 21.7 +/- 2.2%, respectively). Interleukin-2 production by stimulated mononuclear cells was higher in the NT+ compared with the NT- group at 2 months of age (0.90 +/- 0.28 U/mL, 0.27 +/- 0.11 U/mL, respectively); neither formula-fed group differed significantly from the breast-fed group. Rate of growth and incidence and severity of infections did not differ significantly among dietary groups. Nucleotides may be a component of human milk that contributes to the enhanced immunity of the breast-fed infant.