Influenza viruses belong to the Orthomyxoviridae family and cause acute respiratory distress in humans. The developed drug resistance toward existing drugs and the emergence of viral mutants that can escape vaccines mandate the search for novel antiviral drugs. Herein, the synthesis of epimeric 4'-methyl-4'-phosphonomethoxy [4'-C-Me-4'-C-(O-CH2 P═O)] pyrimidine ribonucleosides, their phosphonothioate [4'-C-Me-4'-C-(O-CH2 P═S)] derivatives, and their evaluation against an RNA viral panel are described. Selective formation of the α- l-lyxo epimer, [4'-C-(α)-Me-4'-C-(β)-(O-CH2 -P(═O)(OEt)2 )] over the β- d-ribo epimer [4'-C-(β)-Me-4'-C-(α)-(O-CH2 -P(═O)(OEt)2 )] was explained by DFT equilibrium geometry optimizations studies. Pyrimidine nucleosides having the [4'-C-(α)-Me-4'-C-(β)-(O-CH2 -P(═O)(OEt)2 )] framework showed specific activity against influenza A virus. Significant anti-influenza virus A (H1N1 California/07/2009 isolate) was observed with the 4'-C-(α)-Me-4'-C-(β)-O-CH2 -P(═O)(OEt)2 -uridine derivative 1 (EC50  = 4.56 mM, SI50  > 56), 4-ethoxy-2-oxo-1(2H)-pyrimidin-1-yl derivative 3 (EC50  = 5.44 mM, SI50  > 43) and the cytidine derivative 2 (EC50  = 0.81 mM, SI50  > 13), respectively. The corresponding thiophosphonates 4'-C-(α)-Me-4'-C-(β)-(O-CH2 -P( S)(OEt)2 ) and thionopyrimidine nucleosides were devoid of any antiviral activity. This study shows that the 4'-C-(α)-Me-4'-(β)-O-CH2 -P(═O)(OEt)2 ribonucleoside can be further optimized to provide potent antiviral agents.