The BB rat strain spontaneously develops diabetes mellitus which rapidly progresses to ketoacidosis and death if not treated with exogenous insulin. 4 0 -60% of BB rats develop overt diabetes and exhibit prominent insulitis, selective pancreatic beta cell destruction, and circulating antibodies to islet cell surfaces (1, 2). Diabetes can be prevented with multiple forms of immunotherapy and can be transferred with activated splenic iymphocytes (3, 4). In addition to the diabetic syndrome, BB rats have a striking lymphophenia characterized by an almost total lack of circulating T cells (5). Colleet al. (6-8), using a sequential breeding program, have described associations between the development of diabetes and the inheritance of major histocompatibility complex (MHC) 1 genes, lymphopenia, and susceptibility to pancreatic lymphocytic infiltrates.One of us (R. M. W.) initiated a breeding program, different from that of Dr. Coile and co-workers, to isolate the BB rat's diabetogenic genes on the genetic background of three inbred rat strains. BB rats were cyclically backcrossedintercrossed then backcrossed with Brown Norway (BN), Lewis (L), and WistarFurth (WF) rats while selecting for diabetes. We studied the expression of lymphopenia and MHC antigens. We will present evidence that at least two independent genes or gene complexes are absolutely necessary for the inheritance of diabetes in these rats. One gene (l), determines the T cell lymphopenia of the BB rat and is not linked to the rat MHC. The second gene (RTI-DM), determines the susceptibility to diabetes and is closely linked to the rat MHC. Materials a n d M e t h o d sBreeding Program. Outbred diabetic BB rats and the animals used in this study were maintained at