A fraction of polycythemia vera (PV) and essential thrombocythemia (ET) cases will, in time, undergo myelofibrotic transformation. In such cases, fibrosis may mask the diagnostic histologic features of the original underlying myeloproliferative neoplasm. Thus, confidently differentiating postfibrotic PV/ET from primary myelofibrosis (PMF) histologically may not be possible. It is controversial whether post-PV/ET myelofibrosis (MF) differs clinicopathologically from PMF, or whether these entities are biologically, clinically, and prognostically indistinguishable. To answer this question, we compared multiple candidate biological, morphologic, and prognostic parameters between 19 postfibrotic ET/PV individuals and 18 PMF individuals. The postfibrotic ET/PV and PMF cases did not differ with regard to clinical outcome, cytogenetic abnormalities, serum lactate dehydrogenase level, peripheral blast count, bone marrow morphology, or grade of reticulin fibrosis. Only JAK2 allele burden, which was higher in the postfibrotic PV/ET population (P=0.011), differed between the 2 groups. Cardinal morphologic features of PMF (ie, marrow cellularity, intrasinusoidal hematopoiesis, osteosclerosis, etc.) were commonly observed in post-PV/ET MF marrow biopsies, and only a minority of post-PV/ET MF marrow biopsies the retained diagnostic features of the primary myeloproliferative neoplasm (panmyelosis in PV and megakaryocytic hyperplasia in ET). Our study indicates that PMF and post-PV/ET MF are clinically and biologically indistinguishable.