2''-C-Methylcytidine (2CMC) is a ribonucleoside with broad-spectrum antiviral activity. It reduces the number of viral plaques in BHK-21 cells infected with dengue type 2, reovirus type 1, West Nile, and yellow fever RNA viruses with EC50 values of 95, 26, 80, and 75 μM, respectively. 2CMC inhibits hepatitis C virus (HCV) replication (EC50 = 2.2 μM in a replicon assay) and protects MDBK cells from infection with bovine virus diarrhea virus (BVDV; EC50 = 2.2 μM) and human coronavirus (HCoV; EC50 = 90 μM). It also reduces infectious virus yield in BHK-21 cells infected with foot-and-mouth disease virus (FMDV; EC50 = 6.4 μM) and swine vesicular disease virus (SVDV; EC50 = 45.2 μM). In vivo, 2CMC reduces viral shedding to undetectable levels in a mouse model of persistent norovirus infection.