Polycythemia vera (PV) is a myeloproliferative disorder characterized by an increased proliferation of all three myeloid lineages. The molecular pathogenesis of PV is unknown. Using cDNA microarrays comprising 6000 human genes, we studied the gene expression profile of granulocytes obtained from 11 PV patients compared with granulocytes obtained from healthy individuals. We found that 147 genes were up-regulated by ≥2.5 fold in the majority of PV patients. Eleven of these 147 genes were up-regulated in all PV patients studied and may represent a molecular signature for this disorder. An increase in the expression of several protease inhibitors with affinity for proteases that promote apoptosis in neutrophils (e.g., cystatin F, secretory leukocyte protease inhibitor), as well as the up-regulation of a number of antiapoptotic and survival factors was found (e.g., adrenomedullin, p38 mitogen-activated protein kinase). We speculate that the deregulation of these factors may inhibit normal apoptosis and promote cell survival in the granulocytes of patients with PV. These PV-specific expression changes are likely to be biologically important in the pathophysiology of this disorder.