Liver regeneration after partial hepatectomy is associated with an increase in extrarenal Ep production; however, this surgical procedure is time-consuming and difficult to standardize. Carbon tetrachloride (CCl4) ingestion in rats is an easy and reproducible way to induce liver damage and regeneration. We therefore studied the effects of CCl4 on extrarenal Ep production in rats. Just as is the case following partial hepatectomy, extrarenal Ep production in response to hypoxia was reduced immediately after ingestion of CCl4. Thereafter it rose to supranormal levels which peaked 3 to 4 days after CCl4 ingestion (at this time Ep titers of nephrectomized, CCl4-fed rats rose to greater than 1.0 U/ml of plasma after exposure to 0.42 atmosphere for 7 hr). Extrarenal Ep production then declined, but was still supranormal 7 days after CCl4. Carbon tetrachloride did not significantly affect extrarenal Ep production in rats nephrectomized 18 hr prior to initiation of hypoxia even if they received injections of renin prior to being made hypoxic, nor did it affect Ep production in response to hypoxia in nonnephrectomized rats under the conditions used in this study.