More than 200 hemoglobin variants with high oxygen affinity have been reported since 1966. In about one third of these, the increase in oxygen affinity is responsible for a compensatory erythrocytosis. The degree of erythrocytosis depends primarily upon the molecular defect of the hemoglobin molecule. Measurement of the oxygen binding properties of the blood (or of the stripped lysate) is a convenient test both for the diagnosis of these variants and for evaluation of their severity. In the severe cases the affinity of the abnormal hemoglobin is identical to that of isolated subunits and the heme heme interaction is abolished; erythrocythemia is usually observed. Conversely, when the increase in oxygen affinity is moderate no clinical abnormal features are noticed. A high oxygen affinity variant has to be suspected when the hemoglobin level is at the upper limits of the normal in females or individuals with a mild iron deficiency. Several high oxygen affinity hemoglobins are also unstable and a hemolytic process may mask the increase of the Hb level. These patients, despite Hb levels close to the normal, are anemic from a functional view point. Examples have been reported in the literature in which the high oxygen affinity hemoglobin was found in coincidence with another red cell abnormality: such a situation lead usually to a more severe syndrome than the simple heterozygous state.