We assessed two strains of mice [CD-1 and C3H.HeJ (C3H)] with different responses to coxsackievirus B3 (CVB3) infection at 7, 14, and 21 days after inoculation with 10⁵ pfu of CVB3. CD-1 mice developed inflammatory lesions at 7 days that nearly recovered by 21 days; C3H mice demonstrated persistence of infiltrates. Although there were differences in the baseline fractional shortening, it was further reduced at 7 and 14 days in both strains. It recovered in CD-1 mice but remained depressed at 21 days in C3H mice. Interleukin-6 and tumor necrosis factor- transcripts were increased in both strains at 7 days. Levels dropped to near control in CD-1 mice at 21 days but remained elevated in C3H mice. Interleukin-1 was minimally elevated in CD-1 mice but increased progressively in C3H mice. mRNA for the inducible form of NO synthase (iNOS) was increased at 7 days in the CD-1 mice, returning to baseline by 14 days; it rose progressively in C3H mice, with a fivefold increase at 21 days. We conclude that mice infected with CVB3 show increased expression of proinflammatory cytokines as well as iNOS associated with reduced contractile performance. In more susceptible mice, contractile depression and cytokine and iNOS expression are more pronounced.