We have shown that genetically engineered mengoviruses containing artificially shortened 5' noncoding poly(C) tracts (e.g., C0 or C13UC10) are dramatically attenuated in adult Swiss/ICR mice when compared to wild-type virus or to a genetically engineered virus containing a wild-type length poly(C) tract (C44UC10). To explore further the relationship between poly(C) tracts and virulence, we have conducted more extensive characterizations of several engineered viruses in the murine model. Both short and long poly(C) tract viruses were highly virulent in newborn mice, underscoring the importance of age in poly(C)-mediated attenuation. Virus vMC24, with a tract sequence of C13UC10, was as attenuated in 4-week-old BALB/c, C.C3-H2k/LiMcdJ, and DBA/2 mice as in Swiss/ICR mice. But it was more pathogenic for C57BL/6 mice, and highly virulent for C3H/Hej and C3H/Hen mice, demonstrating the importance of murine genotype. As expected from its virulence in all mouse strains, vMwt, with a poly(C) of C44UC10, induced higher levels of viremia than vMC24. The vMwt also induced higher levels of circulating interferon and had reduced pathogenicity in chemically immunosuppressed Swiss/ICR mice. Similar immunosuppression did not increase the virulence of vMC24. Collectively, the data suggest that endogenous immune components and the immune competence of the host play significant roles in determining the susceptibility of mice to mengovirus infection.