The ability of the peroxisome proliferator WY-14,643 to act as an initiator of hepatocarcinogenesis was examined using a modified growth-selection protocol in rats. Feeding rats 0.1% WY-14,643 in the diet for 3 weeks, coupled with partial hepatectomy after 10 days, failed to initiate the development of growth-selectable foci identifiable by 3 enzyme histochemical stains. Elevation of palmitoyl CoA oxidase activity in WY-14,643 rats from 1 to 11 days after partial hepatectomy suggested tht peroxisome proliferation, even when coupled with hepatocellular DNA replication, did not result in initiation. The failure of WY-14,643 to initiate growth-selectable foci may indicate that promotional activity is important in the hepatocarcinogenicity of the peroxisome proliferators.