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Abamectin (AVM) and ivermectin (IVM) are each metabolized by rat liver microsomes to 3‘‘-O-desmethyl (3‘‘-ODMe), 24-hydroxymethyl (24-OHMe), and 26-hydroxymethyl (26-OHMe) derivatives. Microsomes from rats pretreated with dexamethasone (Dex), but not 3-methylcholanthrene (3MC), increased the formation of 3‘‘-ODMe metabolites of both AVM and IVM. Troleandomycin inhibited formation of 3‘‘-ODMe metabolites by >80% by microsomes from Dex-induced rats. Therefore, cytochrome P450 3A plays a major role in this metabolic pathway. Formation of the 26-OHMe metabolites was markedly increased by microsomes from 3MC-treated but not Dex-treated rats. Formation of 24-OHMe from AVM, but not IVM, was slightly increased by microsomes from 3MC-treated rats. Consistent with this observation, anti-rat cytochrome P450 1A1 inhibited formation of 26-OHMe metabolites of AVM and IVM by 90 and 40%, respectively. This antibody also inhibited formation of the 24-OHMe metabolite from AVM by 60% but not from IVM. Thus, cytochrome P450 1A1 is involved in the hydroxylation of the 26-methyl group of both AVM and IVM as well as the 24-methyl group of AVM but not the 24-methyl group of IVM. Keywords: Avermectin; ivermectin; metabolism; rat; cytochrome P450; isoform