Rat synaptotagmin IV (SYT IV) is a depolarization-inducible synaptic vesicle protein. SYT IV homozygous mutant mice are viable and have deficits in fine motor coordination and some forms of memory. In this study, we report the identification of a human SYT IV orthologue. The predicted amino acid sequence of the human SYT IV clone is nearly 90% identical to the rat and mouse SYT IV proteins. In addition, human SYT IV has a characteristic serine for aspartate substitution within the first C2 domain that is conserved among Drosophila, Caenorhabditis elegans, mouse, and rat SYT IV sequences. The human SYT IV gene maps to chromosome band 18q12.3, a region that defines a break point in the synteny with mouse chromosome 18 and has been implicated by associated markers in two human psychiatric disorders. In the human neuroblastoma cell line SK-N-SH, SYT IV is an immediate-early gene inducible by elevated intracellular calcium and by forskolin, an activator of adenylyl cyclase. Expression of human SYT IV mRNA is restricted to brain and is not detectable in non-neuronal tissues. Within brain, human SYT IV mRNA is most highly expressed in hippocampus, with lower levels present in amygdala and thalamus. These results suggest a role for SYT IV in human brain function and in human neurological disease.