We modelled the driving force for aqueous keto-to-enol tautomerisation of 5-bromouracil, a mutagenic thymine analogue, by first-principles molecular dynamics simulations with thermodynamic integration. Using interatomic distance constraints to model the water-assisted (de)protonation of 5-bromouracil in a periodic water box, we show that the free energy for its enolisation is lower than that of the parent compound, uracil, by around 3.0 kcal/mol (BLYP-D2 level), enough to significantly alter the relative tautomeric ratios. Assuming the energetic difference also holds in the cell, this finding is evidence for the “rare tautomer” hypothesis of 5-bromouracil mutagenicity (and, possibly, that of other base analogues).