We have previously identified the oncogene rgr (ralGDS related) in DNA derived from a rabbit squamous cell carcinoma. Here we describe the identification of the human orthologue of the rabbit rgr gene termed hrgr (human ralGDS related). Four alternatively spliced full-length hrgr transcripts were isolated from normal human testes and liver libraries. Truncation of hrgr confers transforming ability to its cDNA. Using a RT-PCR assay we have been able to detect the expression of an abnormally truncated transcript in several human T-cell lymphoma lines, and in fresh tissue samples of patients with T-cell malignancies. In the DHL cell line, an Anaplastic Large Cell Lymphoma (ALCL) line, a DNA rearrangement was detected within the hrgr gene region. We propose that these T-cell lymphomas, at least in part, owe their malignant phenotypes to genetic alterations of the hrgr gene. These findings also raise the possibility that mutations in the hrgr gene are involved in other malignancies.