The effect of the antidepressant paroxetine on cytosolic free Ca(superscript 2+) concentrations ([Ca(superscript 2+)](subscript i)) in OC2 human oral cancer cells is unclear. This study explored whether paroxetine changed basal [Ca(superscript 2+)](subscript i) levels in suspended OC2 cells by using fura-2 as a Ca(superscript 2+)-sensitive fluorescent dye. Paroxetine at concentrations between 100-1,000 μM increased [Ca(superscript 2+)](subscript i) in a concentration-dependent manner. The Ca(superscript 2+) signal was reduced by 50% by removing extracellular Ca(superscript 2+). Paroxetine-induced Ca(superscript 2+) influx was inhibited by the store-operated Ca(superscript 2+) channel blockers nifedipine, econazole and SK&F96365, and protein kinase C modulators. In Ca(superscript 2+)-free medium, pretreatment with the endoplasmic reticulum Ca(superscript 2+) pump inhibitor thapsigargin abolished paroxetine-induced [Ca(superscript 2+)](subscript i) rise. Inhibition of phospholipase C with U73122 did not alter paroxetine-induced [Ca(superscript 2+)](subscript i) rise. Paroxetine at 10-50 μM induced cell death in a concentrationdependent manner. The death was not reversed when cytosolic Ca(superscript 2+) was chelated with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). Propidium iodide staining suggests that apoptosis plays a role in the death. Collectively, in OC2 cells, paroxetine induced [Ca(superscript 2+)](subscript i) rise by causing phospholipase C-independent Ca(superscript 2+) release from the endoplasmic reticulum and Ca(superscript 2+) influx via storeoperated Ca(superscript 2+) channels in a manner regulated by protein kinase C and phospholipase A2. Paroxetine (up to 50 μM) induced cell death in a Ca(superscript 2+)-independent manner.