O-Benzyl and O-ethyl derivatives of 2''-deoxy-5-(trifuloromethyl)uridine (F3Thd) and 2''-deoxy-5-fluorouridine (FUdR) were synthesized. The oral antitumor activity of the compounds against sarcoma 180 in mice was examined. The 5''-O-ethyl (3b), 5''-O-benzyl (3e), and 3''-O-benzyl (3f) derivatives of F3 Thd were 4-fold more active than F3 Thd itself. Among the substituted -benzyl derivatives of F3 Thd, 3''-O-(p-chlorobenzyl)-F3 Thd(3h) showed the highest activity, with an ED50 less than one-tenth of that of F3 Thd. The activities of 5''-O-benzyl (7c) and 3''-O-benxyl (7d) derivatives of FUdR were equal to those of the effecctive O-alkyl derivatives of F3 Thd.