The retinoblastoma protein-interacting zinc finger gene RIZ maps to the distal short arm of human chromosome 1 (1p36), a region thought to harbor tumor suppressor genes for a variety of human cancers including breast cancer. The RIZ gene normally produces two protein products of different length, RIZ1 and RIZ2. RIZ2 is generated by an internal promoter and lacks an NH₂-terminal motif of RIZ1, the PR domain conserved in a subfamily of zinc finger genes that function as negative regulators of tumorigenesis. We have here studied whether the RIZ gene may play a role in human neoplasia. We found that expression of RIZ1 is commonly decreased or at undetectable levels in breast cancer tissues and cell lines. Decreased RIZ1 expression was also found in other tumor types including neuroblastoma and lung cancer. Remarkably, RIZ2 is normally expressed in all cases examined, suggesting that the abnormality observed for RIZ1 is specific. Forced RIZ1 expression in breast cancer cells caused cell cycle arrest in G₂-M and/or programmed cell death. These observations suggest an exclusive negative selection for RIZ1 but not RIZ2 in breast cancer and a role for RIZ1 in tumor suppression.