Historically, cytogenetic studies of plasma cell neoplasms have been hampered by the fact that terminally differentiated plasma cells do not proliferate well in vitro. Although the use of interphase FISH (iFISH) has greatly improved the ability to detect cytogenetic abnormalities, cases with low numbers of neoplastic cells often do not demonstrate abnormalities. Using a four-assay, nine-probe iFISH panel, we compared the abnormality detection rate for overnight unstimulated bone marrow cultures (ONC) to that for plasma-cell enriched fractions obtained with use of CD138-coated immunomagnetic beads (PCE). In the ONC, an abnormality was detected in 11 of 29 cases (38%); in the PCE, an abnormality was detected in 30 of 33 cases (91%). For 28 cases in which iFISH results from ONC were compared directly with PCE samples, the overall abnormality rate was 36% for ONC and 89% for PCE (P < 0.01). The conventional GTG-banded chromosome analysis revealed only 2 of 34 cases with an abnormal karyotype (6%); both cases were hyperdiploid. We conclude that the plasma cell enrichment step for iFISH should be incorporated into the routine cytogenetic work-up for all patients with plasma cell neoplasms.