The lineage and stage specificity of human isotype switch recombination was investigated by examining the IgH gene configuration in 61 hemopoietic malignancies representing different stages of B and T cell development. An unexpectedly high frequency (20%) of IgM-producing B cell leukemias and lymphomas had undergone C(H) gene rearrangements and deletions consistent with attempted switch recombination. These C(H) gene alterations were found on productive, non-productive, and 14q+ chromosomes. These data support the concept of a non-specific (common) switch recombinase activity that is often ineffective. No evidence of such switch recombination was found in 25 μ- or μ+ pre-B cell leukemias with the single exception of a μ- pre-B leukemia in which subsets of the cells were producing γ- or α-H chains. The switch recombinase activity may be restricted to the B cell lineage, inasmuch as C(H) gene deletions were not observed in T lineage malignancies.