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Simple Summary: JAK2 V617F is a somatic mutation related with myeloproliferative neoplasm (MPN) and it is associated with the germline GGCC (46/1) haplotype. Nowadays, there are no studies focused on the association between the JAK2 haplotype GGCC_46/1 and the onset of onco-drug resistance. Thus, we looked for the haplotype 46/1 in JAK2V617F-positive patients, and we studied their therapy response. Most of the patients with onco-drug resistance had the C/G allele. Instead, the G risk allele, represented by few patients because of its reduced frequency in the general population, was shown to be associated with MPNs' evolution to myelofibrosis and to onco-drug resistance clinical parameters. These findings represent a significant advance in MPN management, although an in-depth analysis on a larger sample is required. We believe that the integration of a comprehensive genetic profiling into treatment decisions may influence the disease progression, prognosis, and treatment efficacy. Background: JAK2 V617F is a somatic mutation associated with myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In MPNs, this mutation is associated with the germline GGCC (46/1) haplotype. Several studies associated JAK2 haplotype GGCC_46/1 with some MPNs clinical parameters, but not one explore the link between JAK2 haplotype GGCC_46/1 and onco-drug resistance. Thus, we assessed for the JAK2 46/1 haplotype's correlation with therapy response in JAK2 V617F-positive patients. Methods: Patients with MPN, selected by the Hematology Laboratory of "V. Fazzi" Hospital (LE), were analyzed with RLFP-PCR assay with rs10974944 SNP. Results: Results show how the majority of patients had PV (63%) or PMF (61%) and that 58% of patients who developed drug resistance had the C/G genotype, while only 11% had the G/G allele. While no direct correlation between JAK2 46/1 haplotype variants and drug resistance was found, the G/G allele was associated with disease progression to myelofibrosis and certain resistance-related clinical parameters (p = 0.002449, odds ratio = 3.701209). Conclusions: Although other analyses are required, due to the narrow cardinality of sample, our findings suggest how the G/G allele could be useful for MPNs diagnosis and for the prediction of the disease outcome. [ABSTRACT FROM AUTHOR]