Recent observations indicate that chromosome aberrations are important prognostic factors in patients with multiple myeloma (MM) treated with high-dose chemotherapy. Nevertheless, the inherent problems of conventional cytogenetics have hampered the systematic evaluation of this parameter in series of patients treated with conventional chemotherapy. Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of numerical chromosomal changes. In the present study, we analyze the relationship between aneuploidies of 15 different chromosomes assessed by FISH and prognosis in a series of 63 patients with MM treated with conventional chemotherapy. After a median follow-up of 61 months (range, 6 to 109), 49% of patients are still alive with a median survival of 33 months. The overall incidence of numerical chromosome abnormalities was 70%. This incidence significantly increased when seven or more chromosomes were analyzed (53 patients), reaching 81%. Trisomies of chromosomes 6, 9, and 17 were associated with prolonged survival (P = .033, P = .035, and P = .026, respectively); by contrast, overall survival (OS) was lower in cases with monosomy 13 (as assessed by deletion of Rb gene, P = .0012). From the clinical point of view, loss of Rb gene was associated with a poor performance status; low hemoglobin levels; high creatinine, C-reactive protein, and lactic dehydrogenase serum levels; high percentage of bone marrow plasma cells (BMPC); extensive bone lytic lesions; and advanced clinical stage. Other chromosome abnormalities such as trisomy of chromosome 9 and 17 were associated with good prognostic features including high hemoglobin levels, early clinical stage, beta2microglobulin less than 6 micro/mL, and low percentage of BMPC. A multivariate analysis for OS showed that S-phase PC greater than 3% (P = .010) and beta2microglobulin serum levels greater than 6 micro/mL (P = .024), together with monosomy of chromosome 13 (P = .031) and nontrisomy of chromosome 6 (P = .048) was the best combination of independent parameters for predicting survival in patients with MM. According to these results, chromosomal analysis is of great use in patients with MM at diagnosis to have a correct prognostic evaluation for clinical decision making.