Circulating levels of the gastric hormone ghrelin rise before and decrease after a meal. In normal-weight subjects, postprandial suppression of ghrelin is proportional to calories consumed. Obese individuals have lower fasting ghrelin levels; however, it is unclear whether the obese show normal postprandial suppression. This study aimed to compare postprandial ghrelin responses in normal-weight and obese subjects, using mixed macronutrient meals with varied fat and calorie content. Postprandial ghrelin response was measured in normal-weight insulin-sensitive subjects and obese insulin-resistant subjects, after six test meals with different fat and calorie content (250-3000 kcal). Increasing the calorie content of meals in normal-weight subjects progressively lowered nadir levels of ghrelin. The obese had lower fasting ghrelin levels, and the reduction after the consumption of all test meals was less than the normal-weight subjects. The lowest postprandial levels in the obese were no different to the nadir in normal-weight volunteers after 1000-, 2000-, and 3000-kcal meals. Thus, circulating ghrelin levels decreased in normal-weight subjects after mixed meals. Obese subjects demonstrated a much reduced ghrelin postprandial suppression. This reduced suppression may influence satiety, thus reinforcing obesity.