A variety of cytogenetic aberrations have been reported in sporadic and familial renal cell carcinoma. Rearrangements of the short arm of chromosome 3 (3p), trisomy 17, and nuclear hyperdiploidy have been reported to be common clonal chromosome changes. We analyzed a total of ten tumor-derived cell lines from patients who underwent nephrectomy for renal cell carcinoma employing conventional cytogenetics. All patients received an immunomodulatory therapy based on recombinant interleukin-2 (rIL-2). Tumor stage and grade, histo- and cytopathology, and patients' response to immunotherapy were assessed and correlated statistically to rearrangement of 3p, trisomy 17, and nuclear hyperdiploidy. Trisomy 17 as clonal aberration could be revealed only in papillary renal cell carcinoma, whereas tumors with compact or tubulopapillary growth pattern lacked this abnormality (p < 0.002). One of 3 patients with diploid or near-diploid karyotype (< or = 49 chromosomes) achieved a partial remission while two presented with stable disease after immunotherapy. In contrast, all 6 patients with tumor progression upon rIL-2-based immunotherapy revealed hyperdiploid (> 49 chromosomes) karyotypes. The correlation between hyperdiploidy and tumor progression was found to be statistically significant (p < 0.029). Interestingly, the only patient achieving an objective tumor remission after immunotherapy presented with a normal diploid karyotype. Our findings suggest tumor hyperdiploidy as an adverse prognostic factor in renal cell carcinoma patients receiving rIL-2-based immunotherapy.