Atracurium, a nondepolarizing muscle relaxant, is eliminated through several pathways, including Hofmann elimination (spontaneous degradation in plasma and tissue at normal body pH and temperature) and ester hydrolysis (catalysis by nonspecific esterases). Because elimination of atracurium occurs in both tissue and plasma, traditional pharmacokinetic models assuming elimination from a single central compartment are inaccurate for atracurium. The authors developed a two-compartment pharnacokinetic model in which hepatic and/or renal elimination occurs from the central compartment (Clorgan), and Hofmann elimination and ester hydrolysis occur from both central and peripheral compartments (Clnonorgan). To determine the in vitro rate constant for Hofmann elimination and ester hydrolysis, atracurium was added to whole blood kept at each patient's pH and temperature. The values for this rate constant ranged from 0.0193 to 0.0238 per min. When these values were applied to the pharmacokinetic model, Cltotal, Clorgan, and Clnonorgan were 4.8 ± 1.1, 3.0 ± 0.9, and 1.9 ± 0.6 ml.kg−1. min−1, respectively. The authors conclude that more than one-half of the clearance of atracurium occurs via pathways other than Hofmann elimination and ester hydrolysis.