Diabetes prone (DP) BB/Wor rats develop spontaneous autoimmune diabetes mellitus caused by a T cell-dependent process that destroys pancreatic beta cells. Neither the inciting immune system defect nor the mechanism by which beta cells are destroyed is known with certainty. DP rats are severely deficient in certain T cell subsets including CD8+ cytotoxic T cells (Tc) and RT6+ T cells. Diabetes-resistant (DR) BB/Wor rats can be rendered diabetic if depleted of RT6+ T cells. To investigate the mechanisms of beta cell destruction in BB rat diabetes, we determined: 1) the relative abundance of Tc and NK cells in the islets of acutely diabetic DP and RT6-depleted DR rats and 2) expression of mRNA encoding cytolysin, a cytolytic pore-forming protein produced by both Tc and NK cells. We found that in the islets of acutely diabetic DP rats NK cells were about three times more abundant than in diabetic RT6-depleted DR rats. Conversely, in the islets of diabetic DR rats, Tc were three times more abundant than NK cells. In addition, cytolysin gene expression was detected in about 60% of the islets of both DP and DR rats. These data suggest that cytolysin may be a mechanism by which Tc and NK cells damage B cells in vivo.