During differentiation B lymphocytes may switch from the expression of surface IgM to the synthesis of IgG, IgA, or IgE isotypes by using a different heavy chain constant region (C(H)) gene. The molecular mechanisms by which switching occurs remain controversial. Rearrangements and deletions of C(H) genes 5' to the expressed gene have often been observed in the mouse and, more recently, in human cells that have switched isotypes. We have used human J(H), C(μ), C(γ), and C(α) probes to examine the extent of the deletions and rearrangements in clones of Epstein-Barr virus-transformed human cells that produce IgG1, IgG3, IgG4, or IgA1. Though deletions of C(H) genes 5' to the expressed C(H) gene were consistently observed, the rearrangement process appeared to be highly variable for the nonproductive C(H) gene locus: deletion or persistence of 5' C(H) genes, combinations of deletion and duplication of 5' genes, and deletions extending to 3' C(H) genes. Our results reveal an unexpected lack of specificity in the DNA deletions in cells that have undergone isotype switching.