Green tea has been receiving considerable attention as a possible neuroprotective agent against neurodegenerative disease. Epigallocatechin-3-gallate (EGCG) is the major compound of green tea. Calcium signaling has profound effects on almost all aspects of neuronal function. Using digital calcium imaging and patch-clamp technique, we determined the effects of EGCG on Ca2+ signals in hippocampal neurons. The results indicated that EGCG caused a dose-dependent increase in intracellular Ca2+ ([Ca2+](i)). This [Ca2+](i) increase was blocked by depleting intracellular Ca2+ stores with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin and cyclopiazonic acid. Furthermore, EGCG-stimulated increase in [Ca2+](i) was abolished following treatment with a PLC inhibitor. However, EGCG inhibited high-voltage activated Ca2+ currents (I-HVA) and NMDA-induced inward currents (I-NMDA). These data suggest that EGCG triggers a cascade of events: it activates phospholipase C (PLC), mobilizes intracellular Ca2+ stores, raises the cytosolic Ca2+ levels, and inhibits the VGCC and NMDA receptors-mediated Ca2+ influx through a process that remains to be determined.