Abnormalities of the TP53 tumor suppressor gene at 17p13.1 are prognostically adverse in a variety of hematolymphoid malignancies. The present study utilized interphase fluorescence in situ hybridization (I-FISH) to detect TP53 deletions and trisomy 12 in 101 clinical specimens from 98 patients with B-cell lymphoproliferative disorders (B-LPDs). Twelve patients had TP53 deletions (group A), 23 had trisomy 12 (group B), and 63 had neither (group C). The groups did not significantly differ in age, duration of disease, absolute lymphocyte count, or percentage with an immunophenotype or cytology atypical for chronic lymphocytic leukemia (CLL). The clinical stage of disease and lactate dehydrogenase (LDH) level were higher in group A, with less response to therapy. After a median follow-up of 19 months, seven of the patients in group A had died of disease (another patient subsequently has had large cell transformation) compared with none in group B and nine in group C. Multivariate analysis found the stage of disease and TP53 deletions as the only parameters independently associated with shortened survival (P < 0.001). Thirty-nine patients had conventional cytogenetic analysis (CCA) which was complexly abnormal in 11 patients; 6 of whom died of disease. There was a trend for complex cytogenetics to be seen more frequently in group A, often with 17p involvement. For most laboratories, CCA may be the preferable initial study to identify prognostically different subgroups of B-LPDs. However, as more probes and clinical outcome data become available, I-FISH will likely play an increasingly important ancillary role.