Decamethylcyclopentasiloxane (D5) is a cyclic polydimethylsiloxane used in the synthesis of silicon-based materials and as a component in consumer products. Male and female Fischer 344 rats were exposed to D5 vapor (0, 10, 40, 160 ppm; whole-body inhalation) for 6 h/d, 5 d/wk, for up to 104 weeks. Microscopic examination of tissues revealed test article effects at 160 ppm in the upper respiratory tract (hyaline inclusions in males and females at 6, 12, and 24 months) and an increased incidence of uterine endometrial adenocarcinoma at 24-months. The hyaline inclusions were considered a non-adverse tissue response for lack of any other respiratory tract non-neoplastic or neoplastic changes. Uterine endometrial adenocarcinoma was not anticipated. Toxicity testing (mutagenicity/genotoxicity, acute, sub-acute and sub-chronic descriptive toxicity) performed prior to the conduct of the chronic bioassay provided no indication that the uterus was a potential target organ. The target organ and tumor type specificity (adenocarcinoma is a common spontaneous tumor in the aged Fischer 344 rat) suggests the effect is associated with estrous cycle alteration. A robust assessment of potential mode(s) of action responsible for the uterine tumors and relevance to humans is addressed in a companion manuscript (Klaunig et al., 2015).