From 1992 to 2000, we identified 23 lymph node biopsies with focal germinal centers (GCs) containing centrocytes staining strongly for bcl-2 protein, whereas most of the remaining lymph node showed bcl-2–negative follicular hyperplasia. We propose the designation in situ localization of follicular lymphoma (FL) for this phenomenon. In 2 additional cases, bcl-2⁺ follicles with features of in situ FL were identified in association with other low-grade B-cell lymphomas. To investigate the clonality of the bcl-2⁺follicles, we performed laser capture microdissection of bcl-2⁺ and bcl-2 follicles from the same lymph node in 5 cases, and analyzed them in parallel by polymerase chain reaction (PCR) amplification of immunoglobulin heavy chain (IgH) genes. In 4 of 5 cases the bcl-2⁺ follicles contained monoclonal IgH gene rearrangements, whereas the bcl-2⁻ GCs exhibited a polyclonal ladder. A BCL2/JH gene rearrangement was detected in 6 of 14 (43%) evaluable cases. There were 5 patients with synchronous evidence of FL at another site. There were 13 patients who, without a prior diagnosis of FL, had clinical follow-up; one developed FL in an adjacent lymph node within one year, and 2 manifested FL at 13 and 72 months, respectively. There are 10 patients who have not yet shown other evidence of FL. These results suggest that at least close to half of these cases (8/18; 44%) represent homing to and early colonization of reactive GCs by FL. Other cases might represent FL at the earliest stage of development, or a preneoplastic event, requiring a second hit for neoplastic transformation. These findings provide insight into the pathophysiology of early FL, and illustrate the utility of immunohistochemistry for early diagnosis.