The therapeutic efficacy of combinations of fluorinated pyrimidines and inhibitors of either ribonucleotide reductase or deoxycytidylate deaminase was evaluated for the treatment of the L1210 mouse leukemia in DBA/2 mice. Therapeutic synergisms were observed with optimal combinations of 5-fluor-2'-deoxyuridine and either hydroxyurea or guanazole. In addition, mice treated with guanazole combined with 5-fluorouracil survived longer than was observed with any dose of guanazole or with 5-fluorouracil alone. Tetrahydrodeoxyuridine, a potential prodrug of a transition-state analog of deoxycytidylate deaminase, did not have antitumor activity by itself nor did it improve the therapeutic response of leukemic mice to 5-fluoro-2'-deoxyuridine. These results are consistent with the hypothesis that deoxyuridylate accumulation was limited by inhibition of ribonucleotide reductase but not by administration of tetrahydrodeoxyuridine. It is suggested that combination chemotherapy with fluorinated pyrimidines and inhibitors of deoxyuridylate synthesis may improve the therapeutic response to these drugs.