Karyotypic studies were performed on methotrexate (MTX)- and vincristine (VCR)-resistant cell lines derived from the human T-cell leukemia CCRF-CEM cell line. We noted karyotypic selection and additional chromosome change associated with acquisition of drug-resistance. Furthermore, we observed that both the parental and MTX-resistant sublines, CEM/MTX R1-3, had a tendency to ploidy change. Karyotypic studies of malignant cells have shown that polyploidy is frequently a consequence of a single sporadic event, followed by growth and selection of the polyploid clone [1]. In this study, however, various karyotypic clones were identified with near- and pseudotetraploid karyotypes that appeared to be derived from different near- and pseudodiploid sidelines. Polyploidy was invariably associated with loss of at least two of the four chromosomes 8 whether the pseudodiploid sideline from which it was derived carried one or both chromosomes 8. In contrast, neither polyploid clones nor loss of chromosome 8 was noted in the CEM/VCR R cells.