Seventeen phthalates were not toxic to female house flies, Musca domestica L., when applied to high dosages topically or by injection. An antagonistic interaction was observed upon simultaneous application of di-2-ethylhexyl phthalate (DEHP) or di-n-butyl phthalate with 21 organophosphates. However, a synergistic interaction was apparent when house flies were pretreated with DEHP by topical application or injection 30 min prior to topical application of organophosphates. Penetration and in vivo and in vitro metabolism studies using DEHP and chlorpyrifos (O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl) phosphorothioate) as model compounds indicated that DEHP, when applied topically to house flies, penetrated extremely slowly and was metabolized very slowly. DEHP also was shown to exert an inhibitory effect on chlorpyrifos metabolism in vitro and in vivo. Chlorpyrifos alone penetrated extremely rapidly and was rapidly metabolized. The antagonistic interaction may be due at least in part to the fact that both DEHP and chlorpyrifos are lipophilic, and the increase in the total lipophilic pool by the DEHP resulted in internal levels of toxicant below the toxicity threshold. A plausible explanation for the synergistic interaction is as follows. Chlorpyrifos penetrated slowly in DEHP pretreated house flies; however, the rate was not as slow as that observed when the two compounds were applied simultaneously. This coupled with the inhibition of chlorpyrifos metabolism by DEHP permitted a slow but lethal accumulation of toxicant.