Colostrum is a complex source of nutrients, immune factors, and bioactive substances consumed by newborn mammals. In previous work, we observed that protein synthesis in the skeletal muscle of newborn piglets is enhanced when they are fed colostrum rather than a nutrient-matched formula devoid of growth factors. To elucidate the mechanisms responsible for this response, we contrasted the fractional rates of sarcoplasmic and myofibrillar protein synthesis of newborn piglets that received only water with those fed for 24 h with colostrum, a nutrient-matched formula, or mature sow's milk. Compared with water, feeding resulted in a 2.5- to 3-fold increase in total skeletal muscle protein synthesis, and this increase was 28% greater in the colostrum-fed than either the formula- or mature milk-fed piglets. Feeding also stimulated muscle ribosome and total polyadenylated RNA accretion. Ribosomal translational efficiency, however, was similar across all fed groups. The greater stimulation of protein synthesis in colostrum-fed pigs was restricted entirely to the myofibrillar protein compartment and was associated with higher ribosome and myosin heavy chain mRNA abundance. Taken together, these data suggest that nonnutritive factors in colostrum enhance ribosomal accretion and muscle-specific gene transcription that, in turn, stimulate specifically the synthesis of myofibrillar proteins in the skeletal musculature of the newborn.