Inhalation exposure for 2 years to 14.3 ppm formaldehyde (HCHO) induced a 50% incidence of squamous cell carcinoma in the nasal cavity of F-344 rats but only a 3.3% incidence in B6C3F1 mice. Since the response was concentration and species dependent, species differences in nasal cavity "dose" were examined as a possible mechanism for the differences in tumor incidence. Naive (nonpretreated) and HCHO-pretreated (6 or 15 ppm, 6 hr/day, 4 days) mice and rats were exposed to HCHO for 6 hr during which respiratory rate and tidal volume were recorded to calculate the theoretical deposition (micrograms/min/cm2) of HCHO on the nasal epithelium. Species differences in delivered "dose" were further assessed by comparative autoradiography, histopathology, and cell turnover studies. Because mice were better able to reduce minute ventilation upon repeated exposures, they had less HCHO available for deposition than rats, resulting in less tissue damage and a lower rate of cell turnover in the nasal epithelium. The correlation between calculated "dose" and observed nasal toxicity, including nasal tumor incidence, demonstrates that by normalizing the dosimetry to nasal surface area, species differences in nasal toxicity may be better understood.