BACKGROUND: Peripheral essential amino acid (EAA) concentrations regulate muscle protein synthesis (MPS). During energy balance, consuming ~9 g EAA doubles postprandial peripheral EAA concentrations and increases resting MPS by nearly 50%. During energy deficit, EAA requirements may be elevated due to a greater carbon skeleton requirement for energy metabolism. We examined if similar or greater increases in peripheral EAA concentrations during energy deficit stimulate the same magnitude increase in MPS as in energy balance. PURPOSE: Determine the effects of peripheral increases in EAA concentrations and the stimulation of MPS during energy balance and deficit. METHODS: Data were derived from two independent controlled studies assessing the effects of consuming high and low doses of EAA on peripheral EAA concentrations and MPS (2H5-phenylanine, direct incorporation method) during energy balance (BAL HIGH/LOW) and energy deficit (DEF HIGH/LOW). In BAL, measures were determined in 8 healthy adults (mean ± SD; 21.4 ± 2 y, 24.6 ± 3.2 kg/m2 ), ingesting in random order, either 4.3 ± 0.0 g or 8.6 ± 0.0 g EAA, separated by 7 d. In DEF, measures followed 5 days of controlled energy deficit (30 ± 4 %) in 19 healthy adults (22.9 ± 5 y, 25.4 ± 2.7 kg/m2), ingesting either 7.8 ± 0.9 g or 23.5 ± 2.6 g EAA, in random order, separated by 14 d. RESULTS: Peak EAA concentrations were 36% higher in DEF HIGH compared to BAL HIGH (2219 ± 470 vs. 1634 ± 320 μmol/L; p<0.05), but not for the low doses. Peak EAA concentrations were higher (p<0.05) in HIGH doses for both energy states compared to LOW doses. Independent of EAA dose, postprandial MPS for BAL (0.78 ± 0.36 %/h) and DEF (0.58 ± 0.15 %/h) were 81% and 26% greater than postabsorptive MPS for BAL (0.43 ± 0.18 %/h) and DEF (0.46 ± 0.24 %/h), respectively (energy-by-fed state, p<0.05). Postprandial MPS was 25% lower in DEF than BAL (energy-by-state, p<0.05). CONCLUSION: Ingesting roughly triple the dose of EAA in DEF than BAL (23.5 g vs. 8.6 g) resulted in marked differences in peripheral concentrations; yet the anabolic stimulus was similar. The reduction in postprandial MPS during DEF, despite ingesting 2-3 times the amount of EAA compared to BAL, suggests that muscle is not the primary target for the greater rise in peripheral EAA. Supported by USAMRDC; authors’ views not official U.S. Army or DoD policy.