The effects of recombinant human leukocyte interferon α-AD on experimental myocarditis caused by coxsackievirus B3 were investigated. Four-week-old male C3H/He mice were inoculated intraperitoneally with 10^5.5 50% tissue culture infective dose (TCD₅₀) in 0.1 ml of coxsackievirus B3 (Nancy strain). Interferon α-AD, 10⁴ U/gm/day, was administered subcutaneously daily, starting 1 day before (group 1) or on the day of (group 2) infection. Animals were killed on day 7. The infectivity of myocardial virus was significantly lower in group 1 (0.7 ± 0.1 log₁₀TCD₅₀/mg, p < 0.005) and in group 2 (2.5 ± 1.2 log₁₀TCD₅₀/mg, p < 0.005) than in control mice (4.4 ± 0.9 log₁₀TCD₅₀/mg). Results of histologic examination showed extensive myocardial necrosis and cellular infiltration in all mice in the untreated group, but significantly less severe necrosis and infiltration in the treated groups. Thus, interferon α-AD, when given before and simultaneously with virus, effectively inhibited replication of myocardial virus and reduced the inflammatory response and myocardial damage in an experimental model of viral myocarditis.