Cytosine arabinoside (1-beta-D-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite used to induce remission in acute leukemia, but cellular resistance to Ara-C reflects a poor prognosis in cancer chemotherapy. To further investigate the mechanisms of resistance to Ara-C, we have established Ara-C-resistant NALM-6 cells. The activation of nuclear factor kappaB (NF-kappaB) was accompanied by the acquisition of Ara-C resistance. Telomerase activity has also increased with the acquisition of Ara-C resistance. The expression of Bid, Bax, or p53 proteins have been shown to increase correlated with the acquisition of Ara-C resistance. In contrast to the increase in these proteins, Bcl-2, Bcl-x, and Bag-1 proteins remained unchanged with the acquisition of Ara-C resistance. Fas expression increased with the acquisition of Ara-C resistance in the late stage. The induction of apoptosis and reduction of cell viability by cytotoxic anti-Fas antibody was more susceptible in resistant cells than parental cells. In conclusion, this report has shown that resistance to Ara-C up-regulates the activation of NF-kappaB, telomerase activity and Fas expression.