Formaldehyde inhalation is linked to nasal cancer and leukemia in humans. Formaldehyde-induced DNA-protein crosslinks and enhanced cell proliferation are important in the pathogenesis of nasal cancer and, potentially, leukemia. Mutations in the tumor suppressor gene Trp53 have been associated with formaldehyde-induced nasal tumors and might be a key mechanistic event in formaldehyde-induced leukemia. The objective of this study was to evaluate the potential role of the Trp53 gene in formaldehyde-induced nasal carcinogenicity, leukemia or lymphohematopoietic cancer, and potentially other neoplasms in genetically susceptible mice. Male Trp53 haploinsufficient (Trp53+) mouse strains (B6.129-Trp53tm1Brd and C3B6.129F1-Trp53tm1Brd) were exposed to 0-, 7.5- or 15-ppm formaldehyde (25/group) 6 h/d, 5 d/wk for 8 wk, and then held for 32 wk. Blood was collected for hematology, and major tissues and gross lesions were collected for histopathology. The primary formaldehyde-related finding was squamous metaplasia of the respiratory epithelium of the nose. Inhalation of a maximum tolerated dose of formaldehyde caused significant injury to the nasal mucosa and cell proliferation, but did not cause nasal tumors or an increased prevalence of leukemia or lymphohematopoietic cancer in Trp53+ mice. All observed neoplasms were considered background lesions for these mouse strains. The results of this short-term carcinogenicity study do not support a role for Trp53 in formaldehyde-induced neoplasia.