We studied the inactivation (by high hydrostatic pressure at 20 o C) of Escherichia coli MG1655 and the selected pressure-resistant mutants that were derived previously from this strain, and which are the most pressure-resistant vegetative cells described to date. The natural antimicrobial peptides, lysozyme (50 μg/ml) and nisin (100 IU/ml), enhanced considerably the inactivation of the target bacteria under pressure. However, kinetic inactivation experiments in the presence of these compounds revealed pronounced tailing, which limited the level of inactivation that could be achieved under mild conditions of pressure and temperature. Interrupted pressure treatments enhanced the effectiveness of lysozyme and nisin, allowing a reduction by at least 6 logs of all strains at 400 MPa. A hypothetical mechanism of 'pressure-promoted uptake' is proposed to explain E. coli outer membrane permeabilization for lipophilic and cationic peptides like lysozyme and nisin under pressure.