Neoplastic transformation of mature B cells can be triggered by class-switch recombination of the immunoglobulin gene, which aberrantly targets a protooncogene and promotes translocation. Class-switch recombination is initiated by the B-cell-specific protein activation-induced cytidine deaminase (AID). Using immunohistochemistry with a newly generated monoclonal antibody and quantitative reverse-transcription-polymerase chain reaction (RT-PCR) on microdissected tissue from lymph node, tonsil, and thymus, we demonstrate that AID expression is found in secondary lymphoid organs outside germinal centers and in the thymic medulla at substantial levels. This is accompanied by the presence of circle transcripts, indicating class-switch recombination to be active at these sites. The dominant AID-expressing cell population outside germinal centers displays cytomorphologic properties corresponding to those that define the recently characterized interfollicular large B-cell subset. These findings indicate that interfollicular large B cells and AID-expressing B lymphocytes of the thymic medulla could give rise to mature B-cell malignancies.