Higher basal concentrations of intracellular calcium (Ca2+) in platelets and lymphocytes from subjects with bipolar affective disorder than in unipolar depressed and healthy subjects implicate abnormal intracellular Ca2+ signaling in bipolar disorder. The purpose of this study was to clarify whether these intracellular Ca2+ abnormalities are trait related. Basal Ca2+ concentration was measured by using ratiometric fluorescence assay with fura-2 for T lymphocytes and Epstein-Barr-virus-immortalized B lymphoblasts from physically healthy subjects with DSM-IV diagnoses of bipolar mood disorder (bipolar I, N= 28; bipolar II, N= 11) or major depressive disorder (N= 14), mixed psychiatric patients with nonmood disorders (N= 14), and healthy subjects (N= 20). Phytohemagglutinin-stimulated (10 µg/ml) intracellular Ca2+ levels were also determined in T lymphocytes. The basal Ca2+ concentration was significantly higher in the B lymphoblasts from patients with bipolar I disorder, but not bipolar II disorder or major depression, than in healthy subjects or psychiatric patients with nonmood disorders. There was a significant interaction between gender and diagnosis in the effect on basal Ca2+ levels in T lymphocytes. Contrasts of diagnoses within gender revealed significantly higher basal Ca2+ concentrations in T lymphocytes in male bipolar I patients, but not men with bipolar II disorder or major depression, than in healthy male comparison subjects. Phytohemagglutinin-stimulated Ca2+ concentrations did not differ among groups, but the percent differences from basal Ca2+ levels were lower in bipolar I and depressed patients than in healthy subjects. These findings support the occurrence of abnormal calcium homeostasis in bipolar disorder and suggest that trait-dependent factors account, at least partly, for the higher basal lymphocyte Ca2+ concentration in bipolar I subjects.