From 50 to 73% of the lithium contained in platelets of patients receiving oral therapy with lithium carbonate was released by brief thrombin treatment. Similarly, about 50% of the lithium in platelets of normal volunteers incubated with lithium chloride was thrombin-releasable. The data indicate that an amount of lithium approximately equal to 10% of the calcium content was sequestered in the dense bodies (amine storage organelles) of human platelets. Electron microprobe analysis of dense bodies suggests that the addition of lithium did not change the phosphorus content but produced a loss of about 10% of the dense-body calcium. Nevertheless, synthetic solid analogues of the dense-body core incubated with lithium chloride did not sequester lithium preferentially over potassium and failed to exchange calcium for lithium. Thus, the mechanism responsible for the observed changes in platelet dense bodies may be related to selective membrane permeability properties rather than to binding of lithium to nucleotides or pyrophosphate in the dense-body core.