BB/Wor diabetes-prone (DP) rats are lymphopenic and frequently develop insulin-dependent diabetes. Diabetes-resistant (DR) BB/Wor rats are not lymphopenic and become diabetic rarely and at a significantly younger age. To examine the genetic basis for diabetes, lymphopenia, and age at onset of diabetes among inbred BB/Wor rats, we crossed nonlymphopenic diabetic rats with lymphopenic DP animals and studied F1, F2, and backcross progeny. F, rats were neither diabetic nor lymphopenic. Diabetes (both types) and lymphopenia reappeared among F2 rats, confirming the permissive association of diabetes and lymphopenia and the recessive nature of both. The absence of diabetes in F1 rats also suggested that the combination of genes responsible for diabetes among lymphopenic and nonlymphopenic rats may be distinct. Nonlymphopenic parental, F1, and F2 rats revealed normal lymphocyte subsets, including CD8+and RT6+ T-lymphocytes. Lymphopenic parental and F2 rats revealed the absence of CD8+ and RT6+ cells, indicating that these T-lymphocyte abnormalities of lymphopenic DP rats segregate with the lymphopenia gene. The distribution of the ages at onset of diabetes among F2 lymphopenic and F2 intercross rats was significantly earlier than among lymphopenic parental and backcross animals, suggesting that the age of diabetes onset is a heritable trait and that the gene(s) or genetic modifier(s) responsible for the earlier onset of F2 diabetes was acquired from the nonlymphopenic parents. Our genetic studies also confirmed the observations that the 2-and 7-kilobase Bam HI fragments of the MHC class I region do not correlate with diabetes or lymphopenia.