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Sarcoptic mange is a highly contagious ectoparasitic disease that causes significant economic losses in the rabbit industry. The current study intended to reveal the infection rate, histopathology, and genetic characterization of Sarcoptes scabiei (S. scabiei) in naturally infected rabbits in Minoufiya governorate, Egypt. A total of 1120 rabbits were physically inspected for sarcoptic mange lesions and infections were confirmed microscopically. In addition, the various hematologic and serum biochemical parameters in naturally infected and non-infected rabbits were evaluated. A histopathological examination was performed. Genomic DNA was isolated from skin scraping samples and amplified using PCR primers targeting the ITS-2 region and Cox1 and Actin genes, which were then sequenced and phylogenetically analyzed. The overall prevalence of S. scabiei was 5.98%. Although the infection was higher in females than males, the analysis showed no statistically significant difference. White blood cells, lymphocytes, liver enzymes (GOT and GPT), urea, total antioxidant capacity, glutathione peroxidase, and malondialdehyde dramatically increased whereas RBCs, Hb, and MCV significantly decreased. There were epidermal thickening and hyperkeratosis, inflammation, and homogenous faint pink edematous lesions, and the S. scabiei was attached to the stratum corneum and/or burrowing through it, causing tunnels. PCR and sequence analysis of the ITS-2 region and Cox1 and Actin genes showed that the sequences in the present study were highly identical to the homologous sequences from several countries and confirmed that the mite was S. scabiei. This study presented the first molecular characterization of S. scabiei in rabbits from Minoufiya Governorate, Egypt., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)