Down Syndrome (DS) caused by trisomy 21 is the most common birth defect associated with mental retardation. Recently, a novel gene named, DSCAM, has been identified in the DS critical region. DSCAM is predicted to be a transmembrane protein with a very high structural and sequence homology to Ig superfamily of cell adhesion molecules and is expressed in the developing nervous system with the highest level in fetal brain. Diverse glycoproteins of cell surfaces and extracellular matrices operationally termed as 'adhesion molecule' are important in the specification of cell interactions during development, maintenance and regeneration of the nervous system. To understand the cellular function of DSCAM protein, we transfected human DSCAM cDNA into mouse fibroblast L cells and analysed its expression. On Western blot analysis, antibodies raised against recombinant DSCAM-Ig3 recognized a 198 kDa protein band in the membrane fraction of DSCAM transfected L cells. Stable transformants expressing DSCAM showed uniform surface expression. DSCAM-expressing transfectants exhibited enhanced adhesive properties, aggregating with faster kinetics and forming aggregates in a homophilic manner. Divalent cations are not required for this cell aggregation. These results demonstrate that DSCAM is a cell adhesion molecule that can mediate cation-independent homophilic binding activity between DSCAM expressing cells.