The drs gene was isolated as a transformation suppressor against the v-src oncogene. Drs protein has a transmembrane domain and three consensus repeats (CRs) called Sushi motifs in the extracellular domain. The drs gene also has the ability to suppress anchorage-independent growth of human cancer cell lines. In this paper, we report the isolation of a novel variant cDNA of mouse drs (mDRS-2) containing two CRs, in addition to a mouse homolog of drs (mDRS-1) containing three CRs. We investigated the suppressor function of these mDRS cDNAs in human cancer cells and found that the lack of one CR is critical for suppression of anchorage-independent growth by drs.