It is generally accepted that suppression of apoptosis in chemically initiated hepatocytes results in promotion of rodent hepatocarcinogenesis. Using immuno-histochemical methods, I studied the expression of Bcl-2, an anti-apoptotic protein, in hepatocellular tumors of B6C3F1 mice. Although normal mouse hepatocytes did not express detectable amounts of Bcl-2, most diethylnitrosamine-induced tumors were positive for this protein. Virtually all of the Bcl-2-positive tumors were composed of small basophilic hepatocytes, whereas the rare cases of Bcl-2-negative tumors demonstrated an eosinophilic appearance. To confirm this difference, tumors initiated with diethylnitrosamine and promoted by phenobarbital were also studied, as this initiation-promotion protocol has been shown to selectively produce eosinophilic lesions. All such tumors were immunohistochemically negative for Bcl-2. The relatively infrequent basophilic tumors found with phenobarbital treatment, however, did express Bcl-2. Thus, the concordance with basophilia was observed regardless of the nature of the promotion agent. These results indicate that the two types of tumors are qualitatively distinct and may develop through independent mechanisms.