Thiopental-14C (30 mg and 10 μCi/kg) was injected intravenously into rats 36–48 hours following bilateral nephrectomy and one minute after pretreatment with sulfadimethoxine (30 mg/kg, iv). Control groups of normal and sham-operated animals were used. The distributions of radioactivity in plasma, brain, and heart 1.5, and 30 minutes after injection were examined. Uremic and sulfonamide-pretreated rats showed significantly higher levels of14C in brain and heart and more free thiopental in plasma at each time than did control animals. There was a significant correlation between the free thiopental in plasma and total drug concentrations in the brain and heart. Uremie rats bound less thiopental in plasma compared with controls in spite of normal total plasma protein and albumin concentrations. It is concluded that reduced protein binding of thiopental leads to accelerated distribution and increased drug concentrations in the brain and heart.