Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, their clinical successes have been limited, oftentimes due to unwanted in vivo metabolic processes that reduce the quantities of nucleoside triphosphate that reach the site of action. In an attempt to circumvent this, we designed novel nucleosides that incorporate a sterically bulky group at the 5'-carbon of the phosphoester prodrug, which we reasoned would reduce the amounts of non-productive PO bond cleavage back to the corresponding nucleoside by nucleotidases. Molecular docking studies with the NS5B HCV polymerase suggested that a nucleotide containing a 5'-methyl group could be accommodated. Therefore, we synthesized mono- and diphosphate prodrugs of 2',5'-C-dimethyluridine stereoselectively and evaluated their cytotoxicity and anti-HCV activity in the HCV replicon assay. All four prodrugs exhibited anti-HCV activity with IC values in the single digit micromolar concentrations, with the 5'(R)-C-methyl prodrug displaying superior potency relative to its 5'(S)-C-methyl counterpart. However, when compared to the unmethylated prodrug, the potency is poorer. The poorer potency of these prodrugs may be due to unfavorable steric interactions of the 5'-C-methyl group in the active sites of the kinases that catalyze the formation of active triphosphate metabolite.