The objective of this study was to assess the combined effects of temperature, pH, sodium chloride (NaCl), and sodium pyrophosphate (SPP) on the heat resistance of Escherichia coli O157:H7 in minced beef meat. A fractional factorial design consisted of four internal temperatures (55.0, 57.5, 60.0 and 62.5. °C), five concentrations of NaCl (0.0, 1.5, 3.0, 4.5 and 6.0. wt/wt.%) and SPP (0.0, 0.1, 0.15, 0.2 and 0.3. wt/wt.%), and five levels of pH (4.0, 5.0, 6.0, 7.0 and 8.0). The 38 variable combinations were replicated twice to provide a total of 76 survivor curves, which were modelled by a modified three-parameter Weibull function as primary model. The polynomial secondary models, developed to estimate the time to achieve a 3-log and a 5-log reduction, enabled the estimation of critical pH, NaCl and SPP concentrations, which are values at which the thermo-tolerance of E. coli O157:H7 reaches it maximum. The addition up to a certain critical concentration of NaCl (~. 2.7-4.7%) or SPP (~. 0.16%) acts independently to increase the heat resistance of E. coli O157:H7. Beyond such critical concentrations, the thermo-resistance of E. coli O157:H7 will progressively diminish. A similar pattern was found for pH with a critical value between 6.0 and 6.7, depending upon temperature and NaCl concentration. A mixed-effects omnibus regression model further revealed that the acidity of the matrix and NaCl concentration had a greater impact on the inactivation kinetics of E. coli O157:H7 in minced beef than SPP, and both are responsible for the concavity/convexity of the curves. When pH, SPP or NaCl concentration is far above or below from its critical value, the temperatures needed to reduce E. coli O157:H7 up to a certain log level are much lower than those required when any other environmental condition is at its critical value. Meat processors can use the model to design lethality treatments in order to achieve specific log reductions of E. coli O157:H7 in ready-to-eat beef products.