Clodronate, one of the halogenated bisphosphonates, was found to inhibit the cell growth of endocytic macrophages, osteoclasts and several cancer cells through diverse mechanisms. Cytosolic Ca2+ signaling had previously been suggested as an apoptotic signal to certain cancer cells. Whether clodronate has an anti-cancer effect and induces the Ca2+ signal in thyroid cancer cells remains unknown. In this study, the effects of clodronate, including growth inhibition and cytosolic Ca2+ signaling, were examined and analyzed on ARO, SW579, WRO and TT thyroid cancer cell lines. Clodronate decreased the growth of these cells in a dose-dependent manner and was more effective on slow growing cells. Clodronate treatment transiently increased cytosolic Ca2+ on slow growing SW579 thyroid cancer cells but not on the fast growing ARO cells. The results from this study implied that clodronate-mediated cell growth inhibition in slow growing thyroid cancer cells might correlate with a Ca2+ signaling pathway.