C5-substituted pyrimidine nucleosides are an important class of molecules that have practical use as biological probes and pharmaceuticals. Herein we report an operationally simple protocol for C5-functionalization of uridine and cytidine via transformation of underexploited 5-trifluoromethyluridine or 5-trifluoromethylcytidine, respectively. The unique reactivity of the CF3 group in the aromatic ring allowed the direct incorporation of several distinct C5-C "carbon substituents": carboxyl, nitrile, ester, amide, and amidine.