Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are two of the mainBCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) characterized by abnormal megakaryocytic proliferation.Janus kinase 2(JAK2) mutations are detected in 50–60% of ET and PMF, whilemyeloproliferative leukemia(MPL) virus oncogene mutations are present in 3–5% of cases. While Sanger sequencing is a valuable diagnostic tool to discriminate the most common MPN mutations, next-generation sequencing (NGS) is a more sensitive technology that also identifies concurrent genetic alterations. In this report, we describe two MPN patients with simultaneous doubleMPLmutations: a woman with ET presenting bothMPLV501A-W515RandJAK2V617Fmutations and a man with PMF displaying an uncommon doubleMPLV501A-W515L. Using colony-forming assays and NGS analyses, we define the origin and mutational landscape of these two unusual malignancies and uncover further gene alterations that may contribute to the pathogenesis of ET and PMF.