Stimulation of cultured human trabecular meshwork cells by histamine caused time and dose related increases in inositol phosphates and intracellular free calcium. The increase in inositol trisphosphate (IP3) was immediate and calcium independent while that of inositol monophosphate (IP1) was gradual and calcium dependent. The rise in intracellular calcium was also rapid and occurred as a result of mobilization from intracellular stores and influx from external medium. Histamine also caused time and concentration related de novo synthesis of inositol phospholipids. Mepyramine but not cimetidine inhibited the action of histamine. These results indicate that histamine, via H1receptor, evokes an early hydrolysis of inositol phospholipids and increase in intracellular free calcium, signals which may be involved with the function of the trabecular meshwork cells.