Male Sprague-Dawley rats were maintained on normal powdered diet or on the same diet containing 10 ppm chlordecone (CD) or 225 ppm phenobarbital (PB) for 15 days. On day 15, they received a single IP injection of a subtoxic dose of CCl4. Induction of cytochrome P-450 was greater with phenobarbital treatment than with chlordecone, but the CCl4-induced destruction of P-450 was similar in both groups and was progressive with the dose of CCl4 and with time after CCl4 administration. CCl4 given to animals on normal diet in a dose range of 25 to 200 microL/kg did not significantly alter the P-450 levels. These findings are consistent with greater bioactivation of CCl4 after the above two pretreatments There was a massive accumulation of Ca2+ in CD- and PB-pretreated animals after CCl4 administration, CD being more effective in this regard. Elevation of cytosolic Ca2+ was progressive despite the mitochondrial and microsomal sequestration of cytosolic Ca2+ at elevated levels. This perturbation of hepatocellular Ca2+ homeostasis which occurs 3 to 6 hr after CCl4 may prevent hepatocellular repair and renovation in CD-treated animals, leading to progressive hepatic lesion, hepatic failure and animal death by 36 to 48 hr at nontoxic doses of CCl4. Neither CD nor PB nor CCl4 alone affected hepatic Ca2+. These findings suggest that excessive Ca2+ accumulation may be related to the progression of hepatotoxic response to CCl4 in CD-treated animals.