Pyrimidines are key components in the genetic code of living organisms and the pyrimidine scaffold is also found in many bioactive and medicinal compounds. The acidities of these compounds, as represented by their pKas, are of special interest since they determine the species that will prevail under different pH conditions. Here, a quantum chemical quantitative structure–activity relationship (QSAR) approach was employed to estimate these acidities. Density-functional theory calculations at the B3LYP/6-31+G(d,p) level and the SM8 aqueous solvent model were employed, and the energy difference ∆EH2O between the parent compound and its dissociation product was used as a variation parameter. Excellent estimates for both the cation → neutral (pKa1, R2 = 0.965) and neutral → anion (pKa2, R2 = 0.962) dissociations were obtained. A commercial package from Advanced Chemical Design also yielded excellent results for these acidities.