A decrease in the pH of the medium facilitated fluoride (F-) influx but depressed its efflux, which is consistent with the hypothesis that simple diffusion of hydrogen fluoride (HF) contributes to F- migration across the cell membrane. Long-term exposure to F- (greater than 1 mM) induced F- accumulation and, as a result, inhibited cell proliferation. In contrast, short-term exposure to F- (greater than 1 mM), followed by careful washing, did not inhibit cell proliferation but rather stimulated it. Moreover, this stimulatory effect was enhanced by 1 microM Al3+ and was inhibited by 1 microM H-7, a specific inhibitor of protein kinase C. Thus F- may stimulate cell proliferation by activating protein kinase C through GTP-binding protein. The stimulatory effect of F- on cell proliferation, which is usually hidden by its inhibitory effect, can be observed by preventing the accumulation of F- in the cytoplasm.