Some coxsackievirus B serotypes are potentially diabetogenic. Previous studies revealed that the virulence and the tissue damage varied with the genetics of the virus strain as well as with the genetics of the mice. A single amino acid variation can alter virulence and tropism in both murine and in vitro models. However, the genetic determinants of this phenomenon have not been determined. In this study, infections with a laboratory strain of coxsackievirus B4 resulted in a diabetes-like syndrome in ICR mice, characterized by chronic pancreatic inflammation together with dysregulation in glucose metabolism, loss of pancreatic acinar tissue and persistent infection in islets. To characterize the genetic determinants involved in the mouse pancreas adaptation, the laboratory strain of coxsackievirus B4 was cloned for molecular characterization. Comparing the whole genome sequence of this virus strain with the other coxsackievirus B4 strains revealed some differences. Altogether 15 nucleotides were changed, resulting in 10 amino acid substitutions, which might be responsible for the pathogenic phenotype of this strain in mice. Anat Rec, 291:601–609, 2008. © 2008 Wiley-Liss, Inc.