Our previous studies demonstrated that manumycin (a farnesyltransferase inhibitor) enhanced the antineoplastic activity and induction of apoptosis when combined with paclitaxel against anaplastic thyroid cancer cells. We found that manumycin induces endogenous expression of p21 Waf-1 in anaplastic thyroid cancer cells. Manumycin increased the activity of the p21promoter, the level of p21mRNA, and the amount of p21 protein. We hypothesized that p21 had a proapoptotic effect in cells treated with manumycin, or paclitaxel, or both agents. By measuring viability and caspase-3 activity, we found that stably transfected KAT-4 cells with p21 cDNA under the control of a metallothionein promoter were more sensitive to manumycin alone, paclitaxel alone, and manumycin plus paclitaxel when p21was induced. The increased sensitivity of the cells with induced p21 was associated with an increase in caspase-3 activity (i.e. apoptosis). We also found that cells with both p21 alleles deleted were less sensitive to manumycin plus paclitaxel than its wild-type parent cells. Expression of p21 per se did not induce apoptosis but enhanced the cytotoxic effects of manumycin and paclitaxel. These findings suggested that p21 might be required to maintain cell sensitivity to the cytotoxic effects of manumycin and paclitaxel.