Male and female BALB/c mice were inoculated with various concentrations of coxsackievirus, group B, type 3 (CVB3), ranging from 10 to 10 (7) plaque-forming units (PFU). Lower viral doses (greater than 10 (2) PFU) induced severe myocarditis in male mice but caused little injury in females. With 10 (7) PFU, females also developed severe disease. Females may be relatively resistant to CVB3-induced myocarditis because virus entry into the blood and heart is less effective. Males given 125I-CVB3 show approximately 2-4 and 20-fold more radioactivity in the peripheral blood and heart, respectively, than females. No differences were observed between the sexes in 125I-bovine serum albumin penetration. Sex steroid hormones influence viremia and virus localization; females given exogenous testosterone and progesterone demonstrate ten times more virus in their hearts than animals given estradiol. The hormones may act by increasing virus receptor expression on endothelial cells and myocytes.