Four different isoforms of mammalian phospholipase C delta (PLC delta) have been described. PLC delta1, the best-understood isoform, is activated by an atypical GTP-binding protein. It has been suggested that it is a calcium signal amplifier. However, very less is known about other subtypes, including PLC delta3. Therefore, in the present study, we examined the expression of PLC delta3 in different human tissues. Moreover, the cellular underlying regulation for PLC delta3 was studied in different cell lines. Our study showed that the mRNA and protein levels differed significantly among human tissues. The human PLC delta3 gene was composed of 15 exons and 1 putative cAMP response element in the 5'-end promoter region. PLC delta3 mRNA expression was downregulated by cAMP and calcium in both the human normal embryonic lung tissue diploid WI38 cell line and the glioblastoma/astrocytoma U373 cell line. However, mRNA expression showed no impact by PKC activators or inhibitors. This study shows the human PLC delta3 expression pattern and is the first report that PLC delta3 gene expression is downregulation by cAMP and calcium.