The catalytic mechanism of orotidine monophosphate decarboxylase (ODCase) has been modeled using density functional theory with the B3LYP functional. Barriers for three different mechanisms have been calculated using large QM and QM/MM models. A concerted protonation mechanism where TS stabilization is provided only by the positive Lys93 has a high barrier around 35 kcal/mol. QM/MM calculations confirm the results obtained using QM models. For a base protonation mechanism, O2 protonation gives a barrier for decarboxylation of 26 kcal/mol. Extensions to this QM model indicate that the cost of protonation may be underestimated and the support for the base protonation mechanism is uncertain. An initial QM/MM investigation of a stepwise mechanism, where water molecules seem to play an important role for TS stabilization, gives the most promising results with an estimated barrier of 22 kcal/mol.