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An antiviral containment strategy for foot-and-mouth disease (FMD) outbreaks could support or replace current contingency plans in case of an outbreak in Europe and could spare many healthy animals from being pre-emptively culled. Recently, substantial progress has been made towards the development of small molecule drugs that inhibit FMD virus (FMDV) replication in vitro. For the initial in vivo evaluation of antiviral lead molecules, a refined FMDV-infection model in guinea pigs (GP) is herewith described. This GP model was validated by demonstrating the antiviral effect of T-1105 (an influenza virus inhibitor with reported activity against FMDV). Sixteen animals were orally administered with T-1105 twice daily (400 mg/kg/day) for five consecutive days and inoculated intraplantarly with 100 GPID50 of the GP-adapted FMDV strain O1 Manisa 1 h after the first administration. The efficacy of T-1105 was compared with that of prophylactic vaccination with a highly potent double-oil emulsion-inactivated O1 Manisa vaccine. Ten animals received a single, full (2 ml) cattle vaccine dose and were inoculated 3 weeks later. Fourteen T-1105-treated and all vaccinated GP were completely protected from generalization of vesicular lesions. At 2 dpi, viral RNA was detected in serum of 9/16 T-1105-treated and of 6/10 vaccinated animals. At 4 dpi, viral RNA was detected in serum, organs and oral swabs of half of the T-1105-treated animals and only in the serum of 1/10 of the vaccinated animals. Mean viral RNA levels in serum and organs of T-1105-treated and vaccinated animals were reduced compared to untreated controls (P