Caffeine administration has been used to stimulate respiration and reverse metabolic alterations in high-birthweight piglets that suffer neonatal asphyxia. However, its effect has not been evaluated on low-birthweight neonates. This study determined the effect of subcutaneously administering caffeine on the physiometabolic profile of neonate piglets with low birthweight and neonatal asphyxia. A 35-mg subcutaneous dose of caffeine, or an equivalent placebo, was randomly administered at 0 and 24 h to neonate piglets (n = 120) diagnosed with intrapartum asphyxia and classified as low-(LW) or high weight (HW) in a 2 by 2 experimental design. Blood samples were obtained at 0, 2 and 24 h postpartum. At 2 h, blood glucose concentrations diminished in the animals in both groups that were treated with caffeine (P < 0.005). Of those animals, only the ones in HW showed increased glucose concentrations by 24 h. At 0 h, group LW exhibited the highest levels of pCO 2 (P < 0.005). In contrast, from 2 to 24 h only the neonates in group HW treated with caffeine reached the levels of pCO 2 and pO 2 characteristic of non-asphyxiated piglets. At the conclusion of the experiment, the weight of the piglets in group LW that were treated with caffeine was less than that of those that received the placebo. In contrast, the weight of the piglets in group HW that were treated with caffeine was 19% higher than that of those which received the placebo (P < 0.005). In this study, administering two doses of 35 mg of caffeine to LW neonate piglets significantly accelerated their energy expenditure, thus reducing their weight gain at 8 days of life; in contrast, the physiometabolic profile of the HW neonate piglets improved and they showed greater weight gain.