Background: Prior evidence suggests that high-calcium intake influences postprandial appetite and insulinemia, possibly due to elevated incretins. In vitro and ex vivo models demonstrate that extracellular calcium and protein synergistically enhance secretion of incretins. This is yet to be shown in humans.Objective: This study was designed to assess energy intake compensation in response to protein and calcium ingestion.Methods: Twenty healthy adults (13 men; 7 women) completed 4 trials in a randomized, double-blind crossover design separated by ≥48 h. During the trials, each participant consumed a low-calcium and low-protein control preload [(CON); 4 g and 104 mg, respectively], a high-protein preload (PRO; 29 g), a high-calcium preload (CAL; 1170 mg), or a high-protein and high-calcium preload (PROCAL). Blood samples were collected at baseline and 15, 30, 45, and 60 min after preload ingestion to determine insulin and incretin hormone concentrations. Energy intake was assessed by a homogenous test meal 60 min after the preload. Visual analog scales were completed immediately before blood sampling to assess subjective appetite sensations.Results: Relative to the CON, the PRO produced 100% (95% CI: 85%, 115%) energy compensation, whereas the CAL produced significant overcompensation [118% (95% CI: 104%, 133%)], which was significantly more positive than with the PRO (P <0.05). The PROCAL resulted in energy compensation of 109% (95% CI: 95%, 123%), which tended to be greater than with the PRO (P = 0.06). The mean difference in appetite sensations relative to the CON was not significantly different between the PRO (−3 mm; 95% CI: −8, 3 mm), CAL (−5 mm; 95% CI: −9, 0 mm), and PROCAL (−5 mm; 95% CI: −10, −1 mm) (P > 0.05).Conclusions: The addition of protein to a preload results in almost perfect energy compensation, whereas the addition of calcium, with or without protein, suppresses appetite and produces overcompensation of subsequent energy intake. The role of circulating insulin and incretin concentrations in these responses, however, remains unclear. This trial was registered at clinicaltrials.gov as NCT01986036.