In patients with cyanosis from congenital heart disease, erythropoiesis is governed by many factors that can alter the expected relation between the oxygen saturation (O_2sat) and hemoglobin concentration. We sought to define the relation between the O_2sat and hemoglobin in such patients and to predict an ideal hemoglobin concentration for a given O_2sat. Adults with congenital heart defects and cyanosis were studied prospectively using blood tests and exercise testing. Nonoptimal hemoglobin was defined as any evidence of inadequate erythropoiesis (i.e., iron, folate, or vitamin B₁₂ deficiency, increased erythropoietin, reticulocytosis, or a right-shifted oxygen-hemoglobin curve). For patients without these factors, a linear regression equation of hemoglobin versus O_2sat was used to predict the optimal hemoglobin for all patients. Of the 65 patients studied, 21 met all the prestudy criteria for an optimal hemoglobin. For all patients, no correlation was found between O_2sat and hemoglobin (r = −0.22). However, a strong linear correlation was found for those meeting the criteria for optimal hemoglobin (r = −0.865, p <0.001). The optimal hemoglobin regression equation was as follows: predicted hemoglobin = 57.5 − (0.444 × O_2sat). A negative correlation was found between the hemoglobin difference (predicted minus measured) and exercise duration on cardiopulmonary exercise testing (r = −0.396, p = 0.005) and the 6-minute walk distance (r = −0.468, p <0.001). In conclusion, a strong relation between O_2sat and hemoglobin concentration can be shown in stable cyanotic patients and used to predict an optimal hemoglobin. This relation might be useful in defining functional anemia in this group.