Gene mutations at the hprt locus were determined in peripheral blood lymphocytes from nine sheep treated with metronidazole (MZ) at therapeutic doses for amebiasis. Pharmacokinetic studies were also carried out, including the calculation of the apparent first-order elimination rate constant (K10) and the steady state concentration of MZ in plasma. Three sheep showed an increase of variant frequencies (Vf) at the hprt locus. A proportional relationship was found between the highest Vf and the highest steady state in plasma, and an inverse relationship between Vf and K10. The finding that the animals with the lowest elimination rates of MZ had increased gene mutations indicates that differences in pharmacokinetics constitute one potential mechanism of genotoxic susceptibility.