Multiple myeloma is an incurable malignant expansion of plasma cells in the bone marrow. Although there is no pathognomonic genetic lesion among multiple myeloma patients, activation of the ras gene has been identified as a common mutation. We have previously described the use of the 3' κ immunoglobulin light chain enhancer (3'KE) to target transgenic expression in murine B and plasma cells, resulting in bcl-X L and c-myc-driven murine models of multiple myeloma. In this report, we characterize the role of activated mutant N-ras in B and plasma cells in transgenic mice. We constructed transgenic mice that use 3'KE to direct expression of a mutant activated N-ras. We also crossed the N-ras mice with mice bearing a c-myc transgene to study the cooperative effects of the transgenic constructs. Mice were sacrificed when moribund or at specific time intervals and characterized by serology, light microscopy, and flow cytometry. The transgenic N-ras animals develop B- and plasma cell lymphoproliferation, and aged mice develop immunoglobulinemia, renal hyaline tubular casts, and microscopic foci of abnormal plasma cells in extramedullary sites, including the liver and kidney. Bitransgenic 3'KE/N-Ras V12 × Eμ-c-Myc mice develop fatal B-cell neoplasia, with a median survival of 10 weeks. These data indicate that activated N-ras can play a role in B- and plasma cell homeostasis and that activated N-Ras and c-Myc can cooperate to induce B-cell neoplasia.