Incorporation of radioactive precursors into DNA, RNA and protein fractions isolated from perfused normal and 22 h regenerating rat livers were measured at temperatures between 37 and 43 degrees C. Compared to the 37 degrees C control levels of precursor incorporation, significant inhibition of precursor incorporation into nucleic acids and protein from slowly and rapidly proliferating livers occurred from 41 degrees to 43 degrees C. The time course of release of newly labeled protein into the perfusate was determined during 1.5 h of perfusion at supranormal temperatures in normal and regenerating liver. Release of radioactive labeled protein into the perfusate was significantly suppressed between 41 degrees and 43 degrees C in a time- and temperature-dependent manner. In both experimental models, the sharpest drop in the rates of precursor incorporation was found between 42 degrees C and 43 degrees C. It is concluded that hyperthermic perfusion (41 degrees to 43 degrees C) significantly suppresses precursor incorporation into hepatic DNA, RNA and protein in normal and regenerating liver. Moreover, the data indicate that macromolecular processes in regenerating liver are no more sensitive to the stress of hyperthermia than those found in normal liver.