Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I‐III Regulatory, Quality, ManufacturingPostmarketing Phase IV The efficacy of the prodrug C2E5, the pentaethyl ester of diethylenetriaminepentaacetic acid (DTPA), as an orally administered chelator of americium was evaluated in rats. C2E5 enhanced 241Am decorporation over vehicle‐only controls (187 μmol/kg, 14.8 ± 4.2% vs control, 7.1 ± 1.4% injected 241Am, P < 0.05) when administered 1 h after 241Am nitrate contamination by intramuscular (i.m.) injection. Reduction in liver burden was also achieved (375 μmol/kg, 13.1 ± 2.0% vs control, 17.3 ± 2.4% 241Am). Under these conditions, a single C2E5 dose did not match the efficacy of intravenous (i.v.) Ca‐DTPA (26.8 μmol/kg; decorporation 24.5 ± 3.5% and liver burden 10.2 ± 2.7% 241Am). Dividing the 375 μmol/kg C2E5 dose enhanced efficacy (4 × 94.5 μmol/kg C2E5; decorporation 19.7 ± 4.5% and liver burden 11.5 ± 2.8% 241 Am; P < 0.001, P < 0.05 vs control), approaching parity with i.v. Ca‐DTPA. When the contamination model was changed to i.v. or i.m. 241Am citrate injection, C2E5 (75 μmol/kg) enhanced decorporation and reduced liver burden. Higher doses of C2E5 (375 μmol/kg) were comparable with i.v. Ca‐DTPA (26.8 μmol/kg), with liver burdens at 3.2 ± 1.4% and 7.4 ± 2.7%, and decorporation of 43.5 ± 8.9% and 37.4 ± 3.9% i.m. 241Am citrate, respectively. The differences observed in oral C2E5 efficacy relative to i.v. Ca‐DTPA between contamination models may be related to the kinetics of the injected americium complex. C2E5 proved to be an effective decorporation agent for 241Am when orally administered and may be improved by optimized treatment strategies.