The antihistamine, pyrilamine maleate, was fed for up to 2 years to groups of 57 Fischer 344 (F344) rats of each sex at dietary levels of 0, 300, 1500, or 3000 ppm (free base). Eight or nine of these rats per sex and dose group were killed at 65 weeks to analyze hematology and clinical chemistry in all groups and histopathology of control and high-dose animals. Histopathology also was performed on all dead or moribund rats and on all that survived for 2 years. Average daily exposures were 11 to 150 mg/kg pyrilamine compared to human dosages up to 3 mg/kg. Pyrilamine treatment did not reduce survival. Final body weights were reduced relative to controls (mid-dose males, 93%, females, 82%: high-dose males, 82%, females, 70%). The incidences of inflammation of the nasolacrimal duct (chronic in females; suppurative in males), liver cytoplasmic vacuolization (males), and the combination of animals with either liver basophilic or clear cell foci (males) tended to significantly increase with dose. Adrenal pheochromocytomas, mammary gland fibroadenomas, and neoplasms of the clitoral gland, thyroid c-cell, and pituitary gland all tended to decrease with increasing dose in females. In males only preputial gland neoplasms exhibited a similar negative trend. While two ovarian granulosatheca cell benign tumors occurred in high-dose females, these were thought to be a random occurrence. There was no evidence for the carcinogenicity of pyrilamine in F344 rats in the current study.