Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. The aim of this study was to evaluate whether a combination of genetic parameters can improve prediction of outcome irrespective of clinical stage. The prognostic impact of chromosome banding analysis (CBA) in addition to FISH and IgVH mutation status was evaluated. In total, 482 patients were analyzed, but evaluation of prognostic factors was restricted to 399 untreated cases. The prognostic significance of age, white blood cell (WBC) count, IgVH status, and TP53 and ATM deletions was confirmed. In addition, a prognostic impact of translocations involving the IGH@ locus (t(IgH)) and of a complex aberrant karyotype was found. On the basis of these results, we propose a scoring system for overall survival (OS) based on: age >or=65 years, WBC >or=20 x 10(9)/l, unmutated IgVH status, TP53 deletion, t(IgH), and the number of chromosome aberrations observed with CBA. Three risk groups showed considerable differences in OS (94.5% vs. 64.3% vs. 41.1% surviving at 5 years, P < 0.0001). Time to treatment (TTT) can be predicted best by unmutated IgVH status, ATM deletion, t(IgH), and number of chromosome aberrations. Four distinct subgroups were separated with median TTT of 110.7 months, 39.8 months, 19.5 months, and 3.8 months, respectively (P < 0.0001). In conclusion, cytogenetic data from CBA add prognostic information. The proposed scoring systems for OS and TTT based on a combination of genetic markers improve the separation of prognostic subgroups in CLL already early in the course of the disease.