Congenic B10.BR/SgSnJ H-2kTla2mice were infected with a diabetogenic strain of coxsackievirus CB4 to correlate abnormalities of sugar metabolism with virus replication in islets, 64.000-Mr(64K) islet autoantigen expression, 64K antibody development, and pancreas histopathology in early and late infection. Plaque assay was used to measure virus replication, whereas immunoprecipitation of the mouse islet extracts with 64K antibody-positive and -negative human sera measured autoantigen expression and antibody development. The infected mice exhibited blood glucose values below that of the noninfected control animals at 72 h postinfection, this subnormal blood glucose persisted at 6 wk postinfection and later. A baseline expression of the autoantigen was detected in the noninfected mice; however, the infected animals did not overexpress the protein at 72 h postinfection or develop 64K antibodies after infection. Limited virus replication was detected in the islets at 72 h postinfection but not later. Acinar necrosis, but not islet loss due to mononuclear cell infiltration, was evident in the infected mice. The congenic mice did not develop hyperglycemia and appear to be diabetes-resistant, their beta cells were largely preserved. This may be due to limited virus replication in their islets or their failure to overexpress the autoantigen and develop 64K antibodies following the infection. Diabetes-susceptible mice, on the contrary, support active virus replication in their islets. overexpress the autoantigen at 72 h postinfection, and develop 64K antibodies and hyperglycemia following such infection (Gerling et al., 1988, 1991).