JAK2 mutations define polycythemia vera (PV). CALR and MPL mutations are specific to JAK2-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF). We examined the effect of these mutations on long-term disease outcome. 1581 patients from the Mayo Clinic (n=826) and Italy (n=755) were studied. Fifty-eight percent of Mayo patients were followed until death; median survivals were 19.8 years in ET (n=292), 13.5 PV (n=267; HR 1.8, 95% CI 1.4-2.2) and 5.9 PMF (n=267; HR 4.5, 95% CI 3.5-5.7). The survival advantage of ET over PV was not affected by JAK2/CALR/MPL mutational status. Survival in ET was inferior to the age- and sex-matched US population (p<0.001). In PMF (n=428), but not in ET (n=576), survival and blast transformation (BT) were significantly affected by mutational status; outcome was best in CALR-mutated and worst in triple-negative patients: median survival 16 vs 2.3 years (HR 5.1, 95% CI 3.2-8.0) and BT 6.5% vs 25% (HR 7.6, 95% CI 2.8-20.2), respectively. We conclude that life-expectancy in morphologically-defined ET is significantly reduced but remains superior to that of PV, regardless of mutational status. In PMF, JAK2/CALR/MPL mutational status is prognostically informative. Our observations do not support the concept of a disease continuum in JAK2-mutated myeloproliferative neoplasms.