We evaluated interferon (IFN) and ribavirin (RBV) as dual therapy and as part of triple-combination therapies with the iminosugars N-butyl-deoxynojirimycin (NB-DNJ), N-nonyl-deoxynojirimycin, and N-7-oxanonyl-6-deoxymethyl-galactonojirimycin. The ability of these compounds to clear bovine viral diarrhea virus (BVDV), a surrogate model for hepatitis C virus (HCV), from a persistently infected Madin-Darby bovine kidney cells cell line was determined by monitoring the secretion of viral RNA and the infectivity of secreted virions. In the BVDV system, after treatment with IFN-RBV alone, viral rebound was observed immediately after removal of the drugs. In contrast, we demonstrate that a triple drug combination of IFN, RBV, and an iminosugar eradicated the BVDV infection in a time- and a dose-dependent manner, leading to sustained viral clearance. Importantly, in the case of NB-DNJ, the sustained viral clearance was achieved by using physiologically relevant and tolerated drug concentrations. Therefore, the use of a triple-combination therapy that includes an iminosugar may prove to be of greater therapeutic value for the treatment of HCV infection than the use of IFN-RBV alone.