Many low birth weight infants experience failure to thrive. The amino acid, leucine, stimulates protein synthesis in skeletal muscle of the neonate but less is known about the effects of the leucine metabolite, β-hydroxy-β-methylbutyrate (HMB). To determine the effects of HMB on protein synthesis and the regulation of translation initiation and degradation pathways, overnight fasted neonatal pigs were infused with HMB at 0, 20, 100, or 400 µmol•kg body weight (BW)^-1•h^-1 for 1 h (HMB 0, HMB 20, HMB 100, or HMB 400). Plasma HMB concentrations increased with infusion and were 10, 98, 316, and 1400 nmol•ml^-1 in the HMB 0, HMB 20, HMB 100, and HMB 400 pigs. Protein synthesis rates in the longissimus dorsi (LD), gastrocnemius, soleus, and diaphragm muscles, lung, and spleen were greater in HMB 20 than HMB 0 and in the LD were greater in HMB 100 than HMB 0. HMB 400 had no effect on protein synthesis. Eukaryotic initiation factor (eIF) 4E•eIF4G complex formation and ribosomal protein S6 kinase-1 and 4E-binding protein 1 phosphorylation increased in LD, gastrocnemius, and soleus muscles with HMB 20 and HMB 100 and in diaphragm with HMB 20. Phosphorylation of eIF2α and elongation factor 2 and expression of system A transporter (SNAT2), system L transporter (LAT1), muscle RING finger 1 protein (MuRF1), muscle atrophy F-box (atrogin-1), and microtubule-associated protein light chain 3 (LC3-II) were unchanged. Results suggest supplemental HMB enhances protein synthesis in skeletal muscle of neonates by stimulating translation initiation.