Increasing immunological dysfunction (atopy and autoimmunity) in western society may be linked to changes in undetermined environmental agents. We hypothesize that increased exposure to multiple gut worm species promotes stronger immunological regulation. We report here that African children constitutively secrete more immunoregulatory cytokines (interleukin [IL]-10 and transforming growth factor [TGF]-β1) under conditions of hyperendemic exposure to the intestinal nematodes Ascaris lumbricoides and Trichuris trichiura, compared with conditions of mesoendemic exposure. Under conditions of hyperendemic exposure, estimators of combined intestinal nematode infection level relate positively to combined constitutive IL-10 and TGF-β1 production and negatively to total immune reactivity (determined as IL-4, interferon-γ, and cellular proliferative responses to Ascaris or Trichuris helminth antigens, Streptococcus pneumoniae bacterial antigen, or the mitogen phytohemaglutinin). Total immune reactivity and anti-inflammatory cytokine production relate inversely. Our data suggest that gut nematodes are important mediators of immunoregulation. © 2008 by the Infectious Diseases Society of America. All rights reserved.