A term infant presented with mild cyanosis without evidence of hypoxia. Cardiopulmonary disease, polycythemia, and methemoglobinemia were excluded. Standard hemoglobin electrophoresis, including isoelectric focusing, were normal. However, by reverse-phase C4 HPLC, an abnormal globin chain was detected. Analysis of tryptic peptides and amino acid sequence showed that the patient had an amino acid substitution Phe-->Ser at residue 41(C7) in the G gamma chain. This was confirmed by DNA sequencing that demonstrated a point mutation at the expected site in exon 2 of the G gamma gene, accounting for the appropriate change in the codon. This substitution, hemoglobin F-Cincinnati, alpha 2 gamma 2 41(C7) Phe-->Ser, not previously described, presumably decreased oxygen affinity of the hemoglobin. This substitution is very near the heme group and the alpha 1 beta 2 interface and, hence, in a crucial area of the globin chain. Abnormalities of gamma globin chains tend to be overlooked due to their transient presence and trivial clinical symptomatology, or due to "in utero" selection when physiologically abnormal. Mutant hemoglobins with altered oxygen affinity should be included in the differential diagnosis of newborns presenting with cyanosis, in whom all common causes have been excluded.