Using the criteria of virus susceptibility as defined by the 50 percent lethal dose response and the percent cumulative mortality response it was shown that the diabetic mutation db, located on chromosome 4, exerted a particular influence on the host response to CB4 challenge. Neither the yellow obese mutation Ay on chromosome 2 nor the misty coat color mutation located one centimorgan from the db mutation had the same effect on CB4 response. The obese diabetic mutation ob located on chromosome 6 appeared to enhance susceptibility to CB4. However, the high susceptibility of the inbred C57BL/6J line on which the ob mutation is found was apparently a significant contributing factor to the ob mutant high virus susceptibility. The response to CB4 was also a useful criteria to discern differences in the genetic background of closely related inbred lines. Based on the CB4 LD50 values the C57BL/6J inbred line was the most susceptible while the C57BL/Ks inbred line was the most resistant. However, using the percent cumulative mortality response as an index of host resistance, the C57BL/KsJ was the most susceptible and the C57BL/Ks the least. These findings further support the thesis that genetic predisposition to diabetes mellitus, as characterized by the mutation db on chromosome 4 is associated with a particular susceptibility and host response to coxsackie-virus B4. It also illustrates that under specific conditions, comparison of the response to virus challenge can be used as an indicator of genetic differences between closely related inbred lines.