Clomazone may be safely used in cotton to manage weeds when applied following treatments of the organophosphate insecticides phorate or disulfoton. The loss of chlorophyll and carotenoids with 6 days of 100 nM clomazone treatment of cotton seedlings was partially prevented with phorate in hydroponic solution in a rate-dependent manner. In a study to examine the timing of safening from a one-day clomazone (100 nM) treatment, maximum safening was achieved when phorate (50 μM) was applied the same day as clomazone. Phorate decreased metabolism of 14C-clomazone to polar metabolites in excised cotton shoots and shoots of intact cotton plants. Microsomal studies of corn shoots showed an NADPH-dependent/cytochrome P450 reaction was inhibited by phorate. Additional studies with corn microsomes, corn seedlings and cotton seedlings supported the basis of clomazone safening is the inhibition of toxic clomazone metabolism by P450 inhibitors.