The carcinogenic activity of various nickel (Ni) compounds is likely dependent upon their ability to enter cells and elevate intracellular levels of Ni ions. Water-insoluble Ni compounds such as NiS and Ni(3)S(2) were shown in vitro to enter cells by phagocytosis and potently induce tumors in experimental animals at the site of exposure. These water-insoluble nickel compounds are generally considered to be more potent carcinogens than the water-soluble forms. However, recent in vitro studies have shown similar effects for insoluble and soluble Ni compounds. Using a dye that fluoresces when intracellular Ni ion binds to it, we showed that both soluble and insoluble Ni compounds were able to elevate the levels of Ni ions in the cytoplasmic and nuclear compartments. However, when the source of Ni ions was removed from the culture dish, the intracellular Ni ions derived from soluble Ni compound were lost from the cells at a significantly faster rate than those derived from the insoluble Ni compound. Within 10 h after NiCl(2) removal from the culture medium, Ni ions disappeared from the nucleus and were not detected in the cells by 16 h, while insoluble Ni(3)S(2) yielded Ni ions that persisted in the nucleus after 16 h and were detected in the cytoplasm even after 24 h following Ni removal. These effects are discussed in terms of whole body exposure to water-soluble and -insoluble Ni compounds and consistency with animal carcinogenicity studies.