Using the fluorescent indicator Fura 2, we measured the free intracellular calcium ion concentration in blood platelets of patients with untreated mania, bipolar depression, and unipolar depression; patients who had recovered from bipolar depression or mania; and age- and sex-matched controls. The baseline intracellular calcium ion concentration was significantly increased in platelets from patients with mania compared with controls. The free intracellular calcium ion concentration after stimulation with platelet-activating factor and thrombin was significantly higher in platelets of manic and bipolar depressed patients than in all other groups. The degree to which intracellular calcium ion concentration increased over baseline after stimulation was significantly lower in unipolar than in bipolar patients. These findings suggest that platelets of manic and depressed bipolar patients have a similar enhancement of intracellular calcium ion activity that is distinctly different from the decreased ability of platelets of unipolar patients to mobilize intracellular calcium in response to stimulation.