Myeloproliferative Neoplasms (MPNs) are a heterogenous group of hematologic cancers characterized by excessive JAK/STAT signaling. Mutations of JAK2 signaling components are among the most common drivers of MPN, but alterations in Suppressors of Cytokine Signaling (SOCS) proteins have been implicated in MPN pathogenesis and progression. Cullin 5 (Cul5) is an E3 ubiquitin ligase known to work with suppressors of cytokine signaling (SOCS) proteins which regulate the JAK/STAT pathway. Here we report that mice lacking Cul5 in hematopoietic stem and progenitor cells (HSPCs) develop an MPN-like disease with characteristic features including splenomegaly, extramedullary hematopoiesis, thrombocytosis, and anemia. Cul5-deficient HSPCs have higher phospho-STAT5 (pSTAT5) levels following stimulation with IL-3 and outcompete WT HSPCs in bone marrow transplants. Immunoprecipitation of Cul5 in cultured HSPCs showed interactions with STAT5 as well as several well-studied substrate receptors including SOCS2, SOCS6, ASB2, ASB3, ASB6 and CIS, as well as lesser-known WSB1 and LRRC41. Proteome analysis of Lin- Sca-1+ c-kit+ (LSK) cells from Cul5Vav-Cre bone marrow shared many upregulated genes and signatures with MPN patient cells. Finally, treatment with ruxolitinib, a JAK1/2 inhibitor, ameliorated MPN symptoms in Cul5-deficient mice. These studies demonstrate a novel function of Cul5 in hematopoiesis, delineating a contributing role in MPN.