Abstract Previous studies have dealt with the propensity of chlordecone (CD) to potentiate the hepatotoxicity of CCl 4. The effect of this interaction upon CCl 4 lethality has never been reported. The objective of the present study was to evaluate the effect of CD on CCl 4 lethality and several parameters associated with cytochrome P-450 activity. Male Sprague-Dawley rats (150–200 g) were fed powdered diets containing 0 or 10 ppm CD or 225 ppm phenobarbital (PB) for 15 days. On day 15, rats from each group received an i.p. injection of CCl 4 in corn oil and the 48-h LD50 was determined. Additional animals were used to measure hepatic microsomal levels of cytochrome P-450 and aminopyrine demethylase. CD decreased the LD50 of CCl 4 from 2.8 ml/kg to 0.042 ml/kg, representing a 67-fold increase in toxicity, as assessed by lethality. PB in this protocol decreased the LD50 to 1.7 ml/kg, representing a 1.6-fold increase in lethality. However, the induction of cytochrome P-450 and associated parameters of mixed-function oxidase (MFO) activity did not correlate with the lethality data. Hepatic microsomal P-450 was increased over controls by 40% and 76% in CD and PB rats respectively. PB also stimulated aminopyrine demethylase activity to a much greater extent (190%) than CD (49%) relative to controls. These findings provide evidence that the CD-CCl 4 interaction results in a marked increase in CCl 4 lethality, in addition to the previously reported marked increase in hepatotoxicity. These results remain consistent with the proposal that bioactivation is the mechanism underlying enhanced CCl 4 toxicity, but suggest that specific effects of CD upon CCl 4 metabolism may be the pivotal mechanism underlying potentiation.