Background: Empirical evidence has shown that rising obesity rates closely parallel the increased consumption of processed foods (PF) consumption in USA. Differences in postprandial thermogenic responses to a whole-food (WF) meal vs. a PF meal may be a key factor in explaining obesity trends, but currently there is limited research exploring this potential link. Objective: The goal was to determine if a particular PF meal has a greater thermodynamic efficiency than a comparable WF meal, thereby conferring a greater net-energy intake. Design: Subjective satiation scores and postprandial energy expenditure were measured for 5–6 h after isoenergetic meals were ingested. The meals were either ‘whole’ or ‘processed’ cheese sandwiches; multi-grain bread and cheddar cheese were deemed whole, while white bread and processed cheese product were considered processed. Meals were comparable in terms of protein (15–20%), carbohydrate (40–50%), and fat (33–39%) composition. Subjects were healthy women (n=12) and men (n=5) studied in a crossover design. Results: There were no significant differences in satiety ratings after the two meals. Average energy expenditure for the WF meal (137±14.1 kcal, 19.9% of meal energy) was significantly larger than for the PF meal (73.1±10.2 kcal, 10.7% of meal energy). Conclusion: Ingestion of the particular PF meal tested in this study decreases postprandial energy expenditure by nearly 50% compared with the isoenergetic WF meal. This reduction in daily energy expenditure has potential implications for diets comprised heavily of PFs and their associations with obesity.