FOLLICULAR lymphoma, the most common human lymphoma, characteristically has a t(14;18) interchromosomal translocation^1,2. It is typically an indolent disease comprised of small resting B cells, but frequently develops into a high-grade lymphoma^3. The t(14; 18) translocates the Bcl-2 gene, generating a deregulated Bcl-2–immunoglobulin fusion gene^4–8. Bcl-2 is a novel inner mitochondrial membrane protein⁹ that extends the survival of certain cells by blocking programmed cell death^9–11. To determine the oncogenic potential of the t(14; 18) translocation, we produced transgenic mice bearing a Bcl-2–immunoglobulin minigene that structurally mimicked the t(14; 18) (ref. 12). An indolent follicular hyperplasia in these transgenic mice progressed to a malignant diffuse large-cell lymphoma. The long latency, progression from polyclonal to monoclonal disease, and histological conversion, are all suggestive of secondary changes. Half of the immunoblastic high-grade lymphomas had a rearranged c-myc gene. Our transgenic mice provide an animal model for tumour progression in t(14; 18) lymphoma and show that prolonged B-cell life increases tumour incidence.