Between 2015 and 2016, 16 adult Solomon Island leaf frogs ( Ceratobatrachus guentheri ) were evaluated at a zoological institution for proliferative epidermal lesions on the head, and occasionally the dorsum and limbs. In most cases, the lesions were severe enough that they could not be surgically resected. Five frogs were diagnosed histologically with proliferative epidermal lesions consistent with squamous cell carcinoma. Polymerase chain reaction for herpesvirus, papillomavirus, and chytridiomycosis yielded negative results. Transmission electron microscopy and virus isolation of two masses did not identify a virus. Although no specific etiology could be identified, based on the clinical presentation, the number of animals affected, and the negative test results for viral agents, an environmental, husbandry, or genetic component were considered as possible etiologies.