Haemonchus contortus is a gastrointestinal nematode parasite of small ruminants causing haemonchosis characterized by anemia that can lead to death. Highly pathogenic, H. contortus causes major economic losses on farms and affects animal welfare. Control of this parasite relies essentially on the use of anthelmintics from the macrocyclic lactone (ML) family. In dairy sheep farms Eprinomectin (EPR) is the only ML used to treat haemonchosis because it is the only null milk withdrawal anthelmintic molecule currently available. EPR intensive use has led to the recent appearance of cases of resistance that are jeopardizing the control of haemonchosis. Hence, we recently reported eprinomectin-resistant isolates of Haemonchus contortus in 5 dairy sheep farms from the Pyrénées Atlantiques (Jouffroy, S. et al. Parasitology (2023). EPR resistance mechanisms are poorly understood in parasitic nematodes. By combining farm Anthelmintic treatment history with phenotypic, genomic and transcriptomic data, we aim at deciphering the determinant of Eprinomectin resistance and proposing resistant markers. These approaches enabled us to unveil the very high resistance to Eprinomectin of Haemonchus contortus isolates (>30x), but also that the resistant populations selected a narrow Quantitative Trait Locus (QTL) on chromosome V and genes expressed in neuronal tissues, associated with anthelmintic response and implicated in diverse cellular and metabolic functions. Investigations of individual genes deregulated and present on chromosome-V QTL are ongoing.