The skin is composed of a dermis and an epidermis, mainly composed of fibroblasts and keratinocytes, respectively. In vivo, the epidermis is among the tissues showing the lower oxygen pressure (pO2), between 1 and 5%. Below 5% of O2, the tissue is usually considered as hypoxic, even when physiological. In mammals, hypoxia was shown to induce lipid droplets (LDs). Interestingly, avian keratinocytes naturally display numerous LDs, that rearrange during the keratinocyte differentiation process occurring between the basal and the transitional layer of the epidermis. To address if hypoxia could contribute to LDs reorganization, we cultured stem-cell-derived chicken keratinocytes in hypoxia (1% O2) for 65h and compared their LDs contents to cells in normoxia by microscopy. The number and size of LDs increased significantly under hypoxia in keratinocytes. LDs were also induced by hypoxia in primary fibroblasts normally devoid of LDs in normoxia. In addition, we demonstrate that the pUL51 protein from Marek's Disease Virus, an important pathogen of chickens that naturally infects keratinocytes, associates to LDs and that this association correlates with virulence in infected chickens. Altogether, our results demonstrate that hypoxia induces lipid droplets in chicken cells, and that their targeting by pUL51 is linked to MDV virulence in its natural host.