We report molecular mechanics (MM) and molecular orbital (MO) (MNDO, AM1, and PM3) calculations applied to the study of 5-substituted arabinofuranosyluracils (5-X-ara-U)(I) with known antiviral activity. The performance of both methods was related to the crystallographic and ab initio data available. The PM3 results were used in the study of the electrostatic potential surfaces. (MM) has proved to be reliable in the description of the geometries of compounds of this kind, but if the electronic properties are needed it is necessary to use the (MO) method. The (MM) results for the studied compounds were fitted to thymidine, as minimized also by (MM).