Salmonella can survive in low-moisture, high-protein, and high-fat foods for several years. Despite nationwide outbreaks and recalls due to the presence of Salmonella in low-moisture foods, information on thermal inactivation of Salmonella in these products is limited. This project evaluated the impact of water activity (aw), temperature, and food composition on thermal inactivation of Salmonella enterica serovar Agona in defined high-protein and high-fat model food matrices. Each matrix was inoculated with Salmonella Agona and adjusted to obtain a target aw, ranging from 0.50 to 0.98. Samples were packed into aluminum test cells and heated (52 to 90°C) under isothermal conditions. Survival of Salmonella Agona was detected on tryptic soy agar with 0.6% yeast extract. Complex influences by food composition, aw, and temperature resulted in significantly different (P < 0.05) thermal resistance of Salmonella for the conditions tested. It was estimated that the same point temperatures at which the D-values of the two matrices at each aw (0.63, 0.73, 0.81, and 0.90) were identical were 79.48, 71.28, 69.62, and 38.42°C, respectively. Above these temperatures, the D-values in high-protein matrices were larger than the D-values in high-fat matrices at each aw. Below these temperatures, the inverse relationship was observed. A correlation between temperature and aw existed on the basis of the level of fat or protein in the food, showing that these compositional factors must be accounted for when predicating thermal inactivation of Salmonella in foods.