The effects of lead (Pb) on the calmodulin activation of human red blood cell membrane calcium-dependent adenosine triphosphatase (Ca-ATPase) were studied in vitro. It was not possible to exclude EGTA from the hemolyzing buffer and retain Ca-ATPase activity and therefore exact concentrations of Pb in the incubation are not known. Nonetheless, nanomolar concentrations of Pb stimulated Ca-ATPase with or without exogenous calmodulin and none of the Pb concentrations tested (1 nM-100 microM) interfered with the calmodulin stimulation of the enzyme. High concentrations of Pb (greater than 10 microM) inhibited Ca-ATPase activity. It is possible that low concentrations of Pb can interfere with calcium dependent processes but the calcium-regulatory protein, calmodulin, is not susceptible to interference by Pb under the conditions used here.