To test the hypothesis that wild-type p53 regulates the expression of p-glycoprotein.Hep3B cells which lack the expression of both p53 and retinoblastoma tumor suppressor genes because of deletions, were transfected with a wild-type (wt) p53 cDNA and control vector by a liposome method.After G418 selection, stable wt-p53 transformants and control vector transformants (pNeo) were obtained. Northern and Western blot analysis determined the expression of p53 mRNA and protein in wt-p53 transformants, respectively. In wt-p53 transformants, induction of transcriptionally active p53 was confirmed by the increase of P21(waf1/cip1) protein. Levels of P-gp reduced in the cells expressing wild-type p53 were linked to wt-p53 activity. Cytotoxicity assays revealed that the wt-p53 transfectants were more sensitive to doxorubicin and mitomycin compared with the pNeo transformants. Flow cytometry showed that the accumulation of doxorubicin in wt-p53 transfectants was as 13 times as that of the pNeo transformants.Restoration of wt-p53 activity in Hep3B leads to sensitiveness to chemotherapeutic agents because of the decrease of p-glycoprotein expression.