In manually dissected Xenopus oocytes, we found that the replacement of external sodium by Tris, choline, or lithium induced a large membrane depolarization and, in voltage clamp, a large inward current. This current appears to be due to activation of a calcium-dependent chloride conductance since it is reversed near ECl, increased by the removal of external chloride, and can be abolished by an injection of BAPTA or by the removal of external Ca2+. Using the Ca-dependent Cl current as a monitor of Ca concentration at the inner surface of the oocyte membrane, we are led to propose that the removal of external Na+ induces an increase in internal Ca2+ via the activation of a Na/Ca exchanger operating in the reverse mode. This interpretation is supported by the finding that the chloride current is diminished in either 3',4'-dichlorobenzamyl (DCB) or high external [Mg2+]o, both of which are known to block the Na/Ca exchanger, whereas it is increased when Li+, rather than Tris or choline, is used as the substitute for Na. The effect of zero [Na+]o was not obtained in oocytes from which follicular cells were removed by enzymatic treatment. This observation led us to test the possibility that the Na/Ca exchanger was present in the follicle cells and not in the oocyte membrane, assuming that entering Ca2+ could pass into the oocyte through gap junctions. Octanol, which blocks gap junctions, or a high [Ca2+]o both considerably reduced the inward current. While octanol probably blocked the gap junctions directly, we propose that the block by high [Ca2+] was due to an excessive rise of [Ca2+]i in the follicular cells. These results, taken together, indirectly suggest the presence of a Na/Ca exchanger in the follicular cells. These results, taken together, indirectly suggest the presence of a Na/Ca exchanger in the follicle cells of Xenopus oocyte which could contribute to the regulation of the internal Ca concentration of the oocyte before fertilization.