Based on a central composite experimental design, the effects of five factors: pH (4.6–6.6), sodium chloride (NaCl, 0–10%), sodium nitrite (NaNO2, 0–152 ppm), pressure (P, 300–600 MPa) and pressure-holding time (t, 0–10 min) on the inactivation of Listeria monocytogenes by high hydrostatic pressure processing on a simulated meat medium (SMM) were evaluated and quantified. Results showed that L. monocytogenes reductions during pressure treatments ranged from 0 to >6 log cfu/g. A polynomial inactivation model was developed being P, t and NaCl the only significant factors influencing HP-lethality (p ≤ 0.05). Inactivation on SMM increased with the increase in P and t, and a synergistic effect between both factors on process effectiveness was remarked. By increasing NaCl concentration (i.e. lowering aw values), a baroprotective effect on L. monocytogenes cells was evidenced. Besides the well-known effects of technological parameters, this study highlights the relevant influence of meat products formulations on the inactivation of L. monocytogenes induced by HHP processing.