Spores of six species (28 strains) of dairy Bacillus isolates were added to sterile reconstituted skim milk and pressure processed (600 MPa for 60 s at 75°C) using either a water-based pressurizing fluid or silicon oil. Processing temperatures peaked at 88 and 90°C, respectively, for both fluids. For all strains, the log inactivation was consistently higher in the silicon oil than in the water-based fluid. This has potential implications for food safety assessment of combined pressure-temperature processes. High pressure processing causes mild heating during pressurization of both the target sample (i.e., spores) and the pressurizing fluid used for pressure delivery. Primarily, the adiabatic heat of compression of the fluids as well as other heat-transfer properties of the fluids and equipment determines the magnitude of this heating. Pressure cycles run with silicon oil were 7 to 15°C higher in temperature during pressurization than pressure cycles run with the water-based pressurizing fluid, due to the greater adiabatic heat of compression of silicon oil. At and around the target pressure, however, the temperatures of both pressurizing fluids were similar, and they both dropped at the same rate during the holding time at the target pressure. We propose that the increased spore inactivation in the silicon oil system can be attributed to additional heating of the spore preparation when pressurized in oil. This could be explained by the temperature difference between the silicon oil and the aqueous spore preparation established during the pressurization phase of the pressure cycle. These spore-inactivation differences have practical implications because it is common practice to develop inactivation kinetic data on small, jacketed laboratory systems pressurized in oil, with extensive heat loss. However, commercial deployment is invariably on large industrial systems pressurized in water, with limited heat loss. Such effects should be considered in food safety assessments of combined pressure-temperature processes.