Primary systemic amyloidosis (AL) is a protein conformation disorder in which monoclonal immunoglobulin light chains produced by clonal plasma cells are deposited as amyloid in the kidneys, heart, liver, or other organs. Why patients with AL present with amyloid disease that displays such organ tropism is unknown. This study tested the hypothesis that both the light-chain variable region (Ig V(L)) germ line genes used by AL clones and the plasma cell burden influenced AL organ tropism. To assess the renal tropism of some light chains, an in vitro renal mesangial cell model of amyloid formation was used. With reverse transcription-polymerase chain reaction, Ig V(L) genes were sequenced from 60 AL patients whose dominant involved organs were renal (52%), cardiac (25%), hepatic (8%), peripheral nervous system (8%), and soft tissue and other (7%). Patients with clones derived from the 6a V(lambdaVI) germ line gene were more likely to present with dominant renal involvement, whereas those with clones derived from the 1c, 2a2, and 3r V(lambda) genes were more likely to present with dominant cardiac and multisystem disease. Patients with V(kappa) clones were more likely to have dominant hepatic involvement and patients who met the Durie criteria for myeloma (38%, 23 of 60) were more likely to present with dominant cardiac involvement independent of germ line gene use. In the in vitro model, unlike all other AL light chains tested, lambdaVI light chains formed amyloid rapidly both with and without amyloid-enhancing factor. These data support the hypothesis that germ line gene use and plasma cell burden influence the organ tropism of AL. (Blood. 2001;98:714-720)