Somatic recombinational events, including the immunoglobulin heavy chain class-switch, are a normal feature of B-cell maturation. To enable comprehensive and sensitive class-switch analysis in ex vivo human B cells, we have developed multiple digestion–circularization PCR (DC-PCR) techniques for quantifiable detection of switching to all immunoglobulin isotypes. This technology was validated by extensive sequencing of PCR products, tests with control non-lymphoid cells and B-cell lines of known isotypic specificities, and by demonstrating DC-PCR selectivity in a model system. With tonsillar B-cell DNA, switching to γ3, γ1, α1, γ2, γ4 and α2 isotypes was reproducibly detectable among different individuals. Levels of ε switching were relatively low and usually required higher total amounts of template DNAs for detection. Quantitation of α1 class switching in a panel of human tonsillar whole B cells was performed by the internal-competitor approach, and showed a pattern consistent with previous studies on IgA+ tonsillar cells. We demonstrate that these assays can rapidly show germline status or specific switch rearrangements in B lymphoid cell lines.