Our hypothesis is that nitrogen loss in septic neonates is caused by increased muscle proteolysis. Sprague-Dawley rat pups (P7) were injected intraperitoneally with NaCl or 4 mg/kg/BW lipopolysaccharide (LPS) and then sacrificed at 2, 4, 24, and 48 hr. Sepsis syndrome was confirmed by elevated serum tumor necrosis factor (24.6 ng/mL ± 18.4 [LPS] and <1.0 ng/mL [controls]; p < .05). Proteolysis in gastrocnemius/soleus muscle was analyzed by quantitation of tissue tyrosine loss. The neonatal rats injected with LPS had significant media tyrosine release at 24 hr compared to the controls (0.39 ± 0.14 versus 0.25 ± 0.11 μmol tyrosine/g muscle; p < .05). At 48 hr, LPS-induced muscle tyrosine release ceased (0.24 ± 0.04 [control] versus 0.23 ± 0.03 μmol tyrosine/g muscle [LPS]). After 48 hr, gastrocnemium/soleus weight was less in the LPS-injected rats (50.5 ± 4.8 to 31.2 ± 4.0 g; p < .0001). Similar changes were not seen in the extensor digitorum longus, suggesting that some muscles were relatively preserved. Also, LPS resulted in significant weight loss. We conclude that selective muscle proteolysis contributes to nitrogen loss in neonatal sepsis. Although proteolysis abates by 48 hr, short-term injury results in significant muscle-mass deficit.