Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by overproduction of red blood cells. We have performed a comprehensive characterization of blood immune cells for expression of naïve and memory receptors as well as β 2 m-associated and β 2 m-free MHC class I heavy chains, also known as closed and open conformers, respectively, in PV patients and age-matched controls (CTR). We show that the peripheral CD3 + CD8 + T cell pool in PV patients is clearly divided into two discrete populations, a more granular CD3 + CD8 high T cell population enriched in effector-memory CD45RA + T cells (CD8 + T EMRA ) when compared to CTR ( P  < 0.001), and a less granular CD3 + CD8 int T cell population that is completely absent in the CTR group (78 vs. 0%, P  < 0.001) and is a mixture of naïve (CD8 + T N ) and CD8 + T EMRA cells expressing intermediate levels of CD28, i.e., CD3 + CD8 int CD28 int . While the percentage of CD3 + CD8 int T N cells correlated positively with the number of erythrocytes, the percentage of CD3 + CD8 int T EMRA correlated negatively with the number of platelets. Finally, we report that PV patients’ lymphocytes and monocytes display lower levels of closed (W6/32 + ) MHC-I conformers at the cell surface while exhibiting increased amounts of open (HC-10 + ) MHC-I conformers. The implications of this distinctive immune signature are discussed.