Resistance to ivermectin (IVM) dangerously compromises the success of anthelmintic therapy in animal and humans. The mechanisms underlying the development of resistance to IVM involve several factors, among which the nuclear hormone receptor NHR-8 has recently emerged as an important driver in Caenorhabditis elegans and in the ruminant parasitic nematode Haemonchus contortus (1). Interestingly, NHR-8 plays is central in drug protection (2) and lipid homeostasis in C. elegans (3), and exposure to IVM alters lipid metabolism in mammalian cells (4,5) and nematodes (6, 7). We hypothesized that IVM-resistant C. elegans would have altered lipid metabolism through ivermectin exposure and activation of nhr-8 regulatory cascade. We have compared wild-type N2B, IVM10 and nhr-8-deficient C. elegans, using complementary approaches, based on imaging of triacylglycerol content by oil-red staining or Coherent anti-Stokes Raman scattering (CARS) spectroscopy. RNA sequencing analysis were also performed to identify putative changes in gene expression. Our data revealed that triacylglycerol stores were altered by ivermectin resistance. We identified several abnormally expressed genes involved in IVR-10 resistance and in NHR-8 deficient C. elegans that may support the alteration of lipid stores observed in IVR-10 animals. Altered lipid metabolism impacts on fitness and the molecular targets involved in this alteration can be exploited to counteract anthelmintic resistance in parasitic nematodes.