The use of the polymerase chain reaction (PCR) to amplify clonal immunoglobulin heavy-chain (IgH) gene rearrangements appears to be a particularly promising technique for detecting minimal residual disease (MRD). However, a major obstacle to successful implementation of this technique involves the problem of clonal evolution, in which instability of the VHDJH region leads to the generation of further rearrangements of the IgH gene over time. Such clonal evolution results in a high likelihood of false negative results when detecting MRD using clone-specific primers based on the rearrangement present at diagnosis. Since in acute lymphoblastic leukemia (ALL), clonal evolution commonly involves alterations of the VHD joining but not the DJH joining, we have devised a novel PCR strategy to circumvent the problem of false negativity in these evolved leukemias. The strategy, which involves construction of overlapping clone-specific DJH primers for use with a consensus VH segment primer, can be used to amplify both evolved and nonevolved ALL populations with high sensitivity and specificity. The method does not require radioactivity and should prove valuable for improving the effectiveness of PCR-based detection of residual leukemia.