An efficient computational method has been identified that uses B3LYP density functional theory, IEF-PCM solvation modeling with a modified UFF cavity, and Boltzmann weighting of tautomers to predict the site-specific and global pK(a) of DNA nucleobases and their oxidation products. The method has been used to evaluate the acidity of guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp), two highly mutagenic guanine oxidation products. The trend observed for the pK(a) values of Gh (9.64 and 8.15) is consistent with the experimentally observed values for guanidine cation (13.7) and hydantoin (9.16). The pK(a1)(calc) value for deprotonation of Sp cation (Sp(+) --> Sp) is very close to the experimentally observed pK(a1) for 8-oxoG and is consistent with the similarity in their structures. The data suggest that the imide (N7) proton in Sp is considerably more acidic than that in Gh, possibly due to the presence of the through-space electronic effects of the carbonyl group located at C6. This difference in the acidity of Gh and Sp may be an indication of their potential toxicity and mutagenicity in vivo and remains a fertile area for experimental study.