In humans, acute erythroid expansion can lead to maturation of red blood cell (RBC) precursors containing fetal hemoglobin (F red cells). This can occur in patients after recovery from bone marrow transplantation, or in individuals affected by sickle cell or thalassemic syndromes. An accelerated erythroid lineage expansion is also a hallmark of the adaptive response to high altitude hypoxia. To explore the possible effect of this environment on F red cell production, we analyzed RBCs from five subjects during and after 17 days spent at high altitude and investigated the expression of fetal hemoglobin by different methodological approaches. By flow cytometry, we found a moderate increase of circulating F red cells during and after the hypoxia exposure, with respect to control cells analyzed before a stay at high altitude. The increased expression of γ-globin (as the specific subunit contained in F hemoglobin together with α-globin) was further confirmed by immunoblotting of young RBC hemolysates and quantitative RT-PCR of transcripts purified from a reticulocyte-enriched RBC fraction. Thus, in healthy adults the exposure to high altitude hypoxia induces maturation of F red cells at a level higher than under normal condition. The effect appears reduced after return to normoxia.