Background: Multicentric squamous cell carcinoma in situ (MSCCIS) is an uncommon cutaneous disease of middle-aged to older cats, with some cases being linked to papillomavirus infection. The disease course is usually benign. Initial eruption of multifocal, pigmented, hyperkeratotic plaques is typical, with gradual progression to thickly crusted ulcerative lesions. Animal: A 5-year-old male neutered Devon rex cat in apparent good health was initially presented with a 16 month history of over 40 nonpruritic dorsally distributed hyperpigmented patches. Lesions progressed gradually over 2 years to larger, more pigmented, crusted plaques and ulcerated nodules. At 7 years of age the cat developed neurological signs and systemic illness and was euthanized. Methods and results: Initial skin histopathology revealed discrete regions of epidermal and follicular epithelial hyperplasia, with moderate numbers of apoptotic keratinocytes, and mild focal epithelial dysplasia. A diagnosis of erythema multiforme was considered; feline herpesvirus-1 immunohistochemistry was negative. Repeat histopathology 22 months after initial presentation confirmed MSCCIS with foci of invasive squamous cell carcinoma (SCC). Postmortem examination 1 month later revealed SCC within the thoracic wall, lungs and vessels of the thoracic spinal cord and heart base, presumed to be metastases from skin lesions. Fluorescent in situ hybridization of initial and later histopathology samples was positive for Felis domesticus papillomavirus type 2. Immunoreactivity of p16 was prominent within early and late cutaneous lesions and internal SCCs. Conclusions: This case represents an unusual presentation of papillomavirus-associated MSCCIS with extensive lesions, atypical initial histopathology and progression to SCC with distant metastases.