Antiviral compounds were evaluated for efficacy against yellow fever virus (YFV) in a hamster model of YFV-induced liver disease. Challenge with a 102 50% cell culture infectious doses of YFV resulted in a 50–80% mortality rate in female hamsters. Virus was detected by quantitative real-time RT-PCR (QRT-PCR) in liver, kidney, spleen and serum with peak titers on 4–6 days post-viral challenge (dpi). Serum levels of alkaline phosphatase, alanine aminotransferase (ALT), bilirubin, blood urea nitrogen, potassium and creatinine were significantly elevated, while serum levels of albumin, amylase, glucose, calcium, globulin, phosphorus, sodium and total protein were significantly reduced. Packed cell volume and white blood cell count were significantly elevated during the course of the infection. Intraperitoneal treatment of hamsters with 0.5–5 μg/kg/day interferon (IFN) alfacon-1, 100 mg/kg/day viramidine or 50 mg/kg/day ribavirin, initiated 4 h prior to YFV challenge, resulted in significant improvement in survival and serum ALT levels. Treatment with IFN alfacon-1 or ribavirin starting 2 dpi, also significantly improved survival and serum ALT levels in hamsters challenged with YFV. Pre- and post-virus exposure treatment with IFN alfacon-1 was efficacious in improving disease in YFV-infected hamsters.