Polymorphs of L-serine have been studied using ab initio density functional theory for pressures up to 8.1 GPa. The SIESTA code was used to perform geometry optimisations starting from the coordinates derived from high-pressure neutron powder diffraction. Between 0 and 8.1 GPa two phase transitions occur, the first of which takes place between 4.5 and 5.2 GPa and the second between 7.3 and 8.1 GPa. A change in molecular conformation occurs during the I-to-II transition, resulting in a stabilisation in intramolecular energy of 40 kJ mol(-1). There is good agreement between the theoretical and experimental coordinates, and the largest root-mean-square deviation between experimental and optimised structures is 0.121 angstrom. Analysis of the effect of pressure on the intermolecular interactions using the PIXEL method showed that none becomes significantly destabilising as the phase-I structure is compressed. It is proposed that the phase transition is driven by attainment of a more stable conformation and from the reduction in the molecular volume. The second phase transition occurs with only a small change in the hydrogen bonding pattern and no substantial difference in molecular conformation. The effect on the energies of attraction between molecules suggests that this transition is driven by the bifurcation of a short OH center dot center dot center dot O interaction.