Whether primary cutaneous follicular lymphoma (PCFL) may or not represent a cutaneous equivalent to nodal follicular lymphoma (FL) is not determined. We have therefore investigated a series of PCFL to determine if tumoral cells carry or not the t(14;18)(q32;q21) translocation, a cytogenetic hallmark of nodal FL. Thirty cases of PFCL were selected according to the criteria of both the European Organisation for Research and Treatment of Cancer and the World Health Organization with 21 cases classified as grade 1 or 2 and 9 cases as grade 3. First, cutaneous tumors were studied by PCR for the amplification of bcl-2/JH rearrangements and by interphase fluorescence in situ hybridization using a dual color probe spanning t(14;18) breakpoints. Second, we tried to determine the origin of bcl2-JH-positive cells by a parallel bcl2-JH and immunoglobulin heavy chain gene amplification of blood mononuclear cells DNA and of DNA extracted from single microdissected B cells. Bcl2-JH rearrangements were amplified by PCR in skin of 9 of 30 (30%) patients with a similar-sized bcl2-JH rearrangement detected in the blood of 7 of these 9 cases. No t(14;18) breakpoint was detected by interphase fluorescence in situ hybridization analysis of 11 bcl2-JH-negative and 5 bcl2-JH-positive PCFL in contrast with its detection in the secondary cutaneous FL and in the nodal FL cases. Single-cell/multigene analysis showed that no single monoclonal B cells of PCFL carried the bcl2-JH rearrangement. Bystander or nontumoral t(14;18)+ B cells emigrating from blood may account for the detection of bcl2-JH rearrangements within PCFL material. Our study also underlines the diagnostic value of interphase fluorescence in situ hybridization to discriminate between t(14;18)-negative PCFL and extracutaneous FL involving the skin.