A mouse pancreas-adapted variant of coxsackievirus B4 (P-CB4) has been shown to replicate in, and cause an excessive release of insulin from, pancreatic beta cells cultured in vitro. The prototype CB4 strain (JVB Benschoten), from which the adapted variant was derived, although able to replicate in cultured islets does not cause a similar release of insulin from the beta cells. The pancreas-adapted virus has also been shown to cause host cell protein synthesis shut-off in beta cells and to inhibit (pro)insulin biosynthesis. These metabolic changes occur in the absence of cytolytic damage [Szopa et al.: Bioscience Reports 5:63-69, 1985 and Cell Biochemistry and Function 4:181-187, 1986]. To investigate the genetic basis for this beta cell tropism, the complete nucleotide sequence of P-CB4 has been determined and compared to that of the previously published sequence of the prototype CB4 strain (JVB Benschoten) [Jenkins et al.: Journal of General Virology 68:1835-1848, 1987]. Twenty-five nucleotide sequence differences were observed. Of these, six occur in the 5' noncoding region of the genome and 19 in the coding region (resulting in seven amino acid changes). The possible significance of these changes in relation to the beta cell tropism of the pancreas-adapted virus is discussed.