Foot hyperkeratosis is common. They often coincide with fungal infections, are difficult to cure and relapse rates are high. In this case study, longstanding and intractable plantar hyperkeratotic lesions were investigated for potential causative agents by histological examinations, by using human cell culture medium to grow the infected skin tissue, by sequencing ribosomal DNA and whole genome. Aspergillus sydowii was identified as the pathogen in the hyperkeratotic lesions. A peculiars intracellular infection of the fungus appeared to merge with anucleated epithelial cells of the skin, in which not fungal cells but basophilic nucleus-like bodies and abundant fungal proteins were seen in the cells. The composite fungal-human zombie-like cells were found to grow in the culture and in hyperkeratotic lesions, and some were readily transformed to natural fungus. Such zombie cells might play roles in the pathogenesis and recurrences of plantar hyperkeratotic lesions, resistance to antifungal drugs and relapses of the fungal infections.