Distinguishing essential thrombocythemia V617F from polycythemia vera is difficult because of shared mutation and phenotypic characteristics. The World Health Organization suggested hemoglobin and hematocrit values to diagnose polycythemia vera (PV), but their sensitivity and specificity were not tested. Moreover, red cell values do not accurately predict red cell mass, which we use to discriminate essential thrombocythemia V617F from PV. Eighty-three PV and 39 essential thrombocythemia V617F patients were diagnosed based on V617F positivity, chromium-51 red cell mass, and marrow biopsy findings. Red cell values used to construct a receiver operating characteristic analysis determined optimal thresholds for distinguishing essential thrombocythemia V617F from PV. Red cell value frequencies were plotted determining if overlap existed. Chromium-51 red cell mass separated PV from essential thrombocythemia V617F, but red cell values overlapped in 25.0-54.7%. Our data indicate that a significant proportion of PV patients may be underdiagnosed by using only red cell values. A bone marrow biopsy was performed in 199 of 410 (48.5%) and a serum erythropoietin value was measured in 225 of 410 (54.9%) of potential PV patients at our institution. Without isotope studies, marrow biopsies and serum erythropoietin values should improve diagnostic accuracy and become mandatory, but clinical data suggest these tests have not been routinely performed. Therefore, the clinical hematologist must be aware of imperfect accuracy when using only red cell values for distinguishing essential thrombocythemia V617F from PV.