To investigate whether follicular lymphoma has a monoclonal origin, we stained frozen tissue sections from 22 afflicted patients for kappa and lambda light chains with an immunofluorescence technic. F(ab')2 antibody fragments were used to avoid binding by Fc receptors. In 20 cases the lymphoma nodules comprised a monoclonal population of immunoglobulin-producing cells. The nodules were usually surrounded by a normal, polyclonal population of B lymphocytes. Reactive lymphoid follicles were easily differentiated from lymphoma nodules on the basis of clonality. Eight cases contained multiple immunoglobulin heavy chains. All the lymphoma nodules in the same tissue or in multiple tissues in the same patient showed identical light-chain and heavy-chain staining even if different histologic subtypes were identified. Follicular lymphoma is the outgrowth of a single clone of immunoglobulin-bearing cells that retain the tissue-homing characteristics of B lymphocytes.