Two novel rare earth substituted phosphotungstates containing 5-fluorouracil, K 9 (C 4 H 4 FN 2 O 2 ) 2 Nd(PW 11 O 39 ) 2 25H 2 O (FNdPW) and K 9 (C 4 H 4 FN 2 O 2 ) 2 Ce(PW 11 O 39 ) 2 23H 2 O (FCePW), were synthesized and characterized by elementary analysis, FT-IR spectra, X-ray powder diffraction and 1 H NMR. The thermal analysis showed that FNdPW decomposed at 210 and 493 °C, and FCePW decomposed at 223 and 471 °C, both of which had good thermal stabilities. MTT tests were performed to study the antitumor activities against HeLa cells and HepG-2 cells of FNdPW, FCePW, 5-fluorouracil, C 4 H 4 FN 2 O 2 H 2 PW 12 O 40 8H 2 O and K 11 Ln(PW 11 O 39 ) 2 xH 2 O (Ln=Nd, Ce), and their cytotoxicities against HEK 293 cells. The results showed that FNdPW and FCePW possessed higher antitumor activities and lower cytotoxicities than those of 5- fluorouracil and C 4 H 4 FN 2 O 2 H 2 PW 12 O 40 8H 2 O, of which FNdPW exhibited the highest antitumor activates against HeLa cells (EC 50 =3.41×10 −6 mol/L) and HepG-2 cells (EC 50 =6.24×10 −6 mol/L). Thus the introduction of rare earth elements and 5-fluorouracil could significantly enhance antitumor effect of polyoxometalates.