The cytotoxic and clastogenic effects of sodium fluoride during various phases of cell cycle of human cultured diploid fibroblasts were examined. The cells in confluence were synchronized at G1/G0 phase by a period of growth in medium containing 1% serum (low serum medium). To obtain the cells in S phase and G2 phase, exponentially growing cells were cultured in low serum medium with a subsequent blockage of the cells at the G1/S boundary by hydroxyurea. Synchronized cells were treated with sodium fluoride for 3 hr during the G1 phase or G2 phase, and for each of three 3-hr periods during the S phase which lasted 9 hr. The cytotoxicity, as determined by a decrease in colony-forming ability, was dependent upon the phase of cell cycle during which treatment was administered. The highest lethality was observed for treatment in early to middle S phase, whereas scare lethality was observed in G1 phase. Inducibility of chromosome aberrations of the cells following treatment with sodium fluoride was also dependent upon the phase of cell cycle. Significant increase in the incidence of chromosome aberrations was observed only in cultures treated during early and/or middle S phases of the cell cycle. These results indicate that cytotoxicity and clastogenicity of sodium fluoride to cultured human diploid fibroblasts are cell phase dependent, and that the cells in early and middle S phases are more sensitive to these effects.