The differential disposition of hexachlorocyclopentadiene (HCCP) following oral administration, as contrasted to inhalation or intravenous administration, may account for its lower toxicity by this route. Following an intravenous dose [14C]HCCP to rats at 0.59 mg/kg, 39.0% of the radioactivity remained in the tissues at 72 h; after inhalation of vapors of [14C]HCCP (1.3–1.8 mg/kg), this amount was 71.5%. After oral doses of 4.1 or 61 mg/kg, however, the amount was only 2.4%. No detectable amount of intact HCCP was present in the lungs or kidneys of rats exposed to the chemical by inhalation, and only about 1% was converted to CO2, regardless of the route of administration. The chemical reactivity of HCCP with biological materials was evident in in vitro experiments, in which HCCP became bound to components of whole blood, plasma, liver homogenates, fecal homogenates, and intestinal contents. Thus, the lower toxicity of oral doses of HCCP may be related to its reaction with intestinal contents and its lack of absorption into tissues, in substantial amounts, as the intact, reactive form.