Primary cultures of rat hepatocytes were exposed to 3 or 30 microM stable cadmium (Cd) in the presence or absence of 1.8 or 3.6 mM calcium (Ca). The presence of Ca significantly reduced the efflux of lactate dehydrogenase (LDH) from cells regardless of Cd concentration or exposure time. During a 3-h time interval, the influx of Cd into hepatocytes increased from about 5 to 14% of the total extracellular Cd present. The presence of Ca during 30 microM Cd exposures resulted in an 18% reduction (P less than 0.01 or 0.001) in Cd influx during a 3-h exposure. About 11% more Cd was bound to those cells exposed in the absence of Ca following 2-h, but not 0.5-h, exposures. Therefore, binding of Cd to hepatocytes was not related directly to Cd uptake since Cd uptake (but not binding) was elevated at the 0.5-h time interval. Although the presence of Cd did not affect the influx of Ca, the presence of Cd increased the binding of Ca by 557% (P less than 0.001). Interaction between these cations at the same binding and/or entry sites on (or adjacent to) phospholipid head groups could account for the modulatory effect of Ca on Cd-challenged hepatocytes.