Injections of a crude fetal sheep liver extract (FSLE) containing fetal hemoglobin, MPLA, and glutathione (GSSH) reversed cytokine changes in aged mice. To investigate the role of fetal hemoglobin we derived mice with homzygous deletions for either of the two major βchains, Hgbβ _ma KO or Hgbβ _mi KO. Hgbβ _mi is the most prominent fetal Hgbβ chain, with Hgbβ _ma more prominent in adult mice. Mice lacking another fetal Hgb chain, HgbεKO, died in utero. CHO cells transfected with cloned Hgb chains were used to produce proteins for preparation of rabbit heteroantibodes. Splenocytes from Hgbβ _ma KO mice stimulated in vitro with Conconavalin A showed a higher IL-2:IL-4 ratio than cells from Hgbβ _mi KO mice. Following immunization in vivo with ovalbumin in alum, Hgbβ _ma KO mice produced less IgE than Hgbβ _mi KO mice, suggesting that in the absence of Hgbβ _mi KO mice had a predeliction to heightened allergic-type responses. Using CHO cells transfected with cloned Hgb chains, we found that only the fetal Hgb chain, Hgbε, was secreted at high levels. Secretion of Hgbβ _ma or Hgbβ _mi chains was seen only after genetic mutation to introduce the two N-linked glycosylation sites present in Hgbε, but absent in the Hgbβ chains. We speculated that a previously unanticipated biological function of a naturally secreted fetal Hgb chain may be partly responsible for the effects reported following injection of animals with fetal, not adult, Hgb. Mice receiving injections of rabbit anti-Hgbε but not either anti-Hgbβ _ma or anti-Hgbβ _mi from day 14 gestation also showed a bias towards the higher IL-2:IL-4 ratios seen in Hgbβ _mi KO mice.