ABSTRACT: Immune system stimulation (ISS) adversely affects protein and AA metabolism and reduces productivity in pigs. Leucine (Leu) has a regulatory role in skeletal muscle protein turnover, which may be affected by ISS. The objective of this study was to evaluate the effects of ISS and dietary Leu supplementation on the protein fractional synthesis rate (FSR) of various tissues in pigs. Yorkshire barrows were surgically fitted with jugular vein catheters and assigned to one of three dietary treatments: (i) CON, 1.36% standardized ileal digestible (SID) Leu; (ii) LEU-M, 2.04% SID Leu; and (iii) LEU-H, 2.72% SID Leu. The diets were formulated to contain all essential AA 10% above estimated requirements for maximum whole-body protein deposition for this BW range. At the start of the 36-h challenge period (initial BW = 14.5 ± 0.8 kg), ISS was induced in pigs with lipopolysaccharide (ISS+; n = 7, 8, and 7 for CON, LEU-M, and LEU-H pigs, respectively); a subset of CON pigs was injected with sterile saline (ISS-; n = 6). During challenge period, pigs were fed every 4 h and feed intake of ISS- pigs was kept equal to ISS+ pigs. At the end of the challenge period, FSR of liver, plasma, gastrocnemius, and LD proteins were determined with a flooding dose of l-[ring-2H5]phenylalanine (40 mol%). All essential AA, most nonessential AA, and plasma urea-N peaked at 12 h and declined to baseline levels at 36 h after ISS was induced in ISS+ pigs (P < 0.05), whereas plasma AA and urea-N concentrations were constant in ISS- pigs. At 36 h, dietary Leu supplementation resulted in a linear decline in plasma isoleucine, valine, glutamine, and urea nitrogen concentrations (P < 0.05), whereas plasma Leu concentration was unaffected. Liver protein FSR was increased in ISS+ pigs (P < 0.05), whereas plasma and skeletal muscle protein FSR was not affected by ISS. Dietary Leu supplementation tended to diminish liver protein FSR (linear reduction; P = 0.052) and increase gastrocnemius protein FSR (linear increase; P = 0.085) in ISS+ pigs. Leucine supplementation above estimated requirements may support repartitioning of AA from visceral to peripheral protein deposition during ISS.