Octamethylcyclotetrasiloxane (D4) is a cyclic volatile methylsiloxane primarily used in the synthesis of silicon-based materials used in a variety of consumer products. This paper details the chronic toxicity and oncogenicity evaluation of D4 in the Fischer 344 rat. Animals were exposed to 0, 10, 30, 150, or 700ppm D4 vapor for 6h/day, 5days/week for up to 104 weeks in whole-body inhalation chambers. Effects of two year chronic exposure included increased liver, kidney, testes, and uterine weight with correlating microscopic findings of hepatocellular hypertrophy (males only), chronic nephropathy (both sexes), interstitial cell hyperplasia, and cystic endometrial hyperplasia and endometrial adenoma, respectively. Upper respiratory tract irritation and lymphocytic leukocytosis were evident in both sexes. Increased neoplasia was demonstrated only in the uterus. Uterine endometrial adenomas were present in four of sixty animals exposed to 700ppm D4 for 24 months. None were present in the other treatment groups. In contrast, in 700ppm D4 group males the incidence of pituitary and pancreatic neoplasia was reduced as was thyroid c-cell adenoma/carcinoma in 700ppm females. This study has identified that D4 is a mild respiratory irritant and increases liver and kidney weight without inducing neoplasia in these tissues. The increased incidence of uterine adenoma was the only treatment-related neoplastic finding associated with chronic exposure to D4.