Background: Equid alphaherpesvirus-1 (EHV-1) is a frequent respiratory pathogen of the horse, causing mild disease and occasionally myeloencephalopathy (EHM) or abortion. Current vaccines reduce the nasopharyngeal excretion and dissemination of the virus and therefore the extent of an epizooty, but their efficacy against secondary forms of diseases (abortion and EHM) is either limited or remains untested respectively. Several antiviral compounds are active against EHV-1 in vitro but no pharmaceuticals are licenced for in vivo treatment to date. Objectives: To measure the in vivo efficacy of antiviral compounds, starting on the day of experimental infection of the target species with EHV-1 (C2254), as assessed by any reduction of clinical signs, virus shedding and viraemia. Study design: Randomised semi-blinded experiment. Methods: Four ponies were treated with valganciclovir (VGCV, the oral prodrug of ganciclovir [GCV]) at 6.5 mg/kg bodyweight, three times on day 1 and twice daily until day 14 inclusive. Four other ponies received a placebo. All ponies were experimentally infected with a field EHV-1 strain (5e07 TCID50/pony). Clinical signs of disease, virus shedding and blood/cell associated viraemia were recorded and measured for 3 weeks. Results: Serum GCV concentration was maintained above the EC50 (0.153 µg/mL) for at least 15 days. The overall cumulative clinical score was significantly reduced in VGCV treated ponies when compared with controls (p<0.009; pyrexia duration, nasal discharge and coughing). Infectious EHV-1 shedding measured on RK13 cells was significantly reduced in the VGCV treated group when compared with the control group between D+1 and D+12 (p=0.006). Blood and cell-associated viraemia were also both significantly reduced in the VGCV treated group (p=0.02 and 0.03, respectively). All ponies seroconverted after infection.