Traumatic brain injury (TBI) in infants and toddlers is frequently explained by child abuse. This study compared 6-month outcome in children with inflicted TBI (iTBI) or non-inflicted TBI (nTBI) who were injured before 3 years of age, and assessed the relationship between outcome and serum concentrations of neuron-specific enolase (NSE), S100B, and myelin-basic protein (MBP). Children with iTBI (n = 15) or nTBI (n = 15) of varying severity were assessed 6 months after injury using the Glasgow Outcome Scale (GOS), Vinel and Adaptive Behavior Scale (VABS), and an intelligence quotient (IQ) measure. Serum concentrations of NSE, S100B, and MBP were measured soon after injury and every 12 h, for up to 5 days. Groups were matched by ethnicity, gender, socioeconomic status, and injury severity. Student's t-tests, analysis of covariance, or nonparametric tests assessed between-group differences for GOS, IQ, and biomarkers; correlation coefficients assessed relationships between outcome and biochemical markers. Functional and cognitive tests showed significant between-group differences (p < or = 0.05); the iTBI group performed more poorly (GOS, 2.00 +/- 1.00 vs.1.23 +/- 0.60; VABS, 95.92 +/- 14.05 vs. 115.80 +/- 20.02; IQ, 69.00 +/- 20.85 vs. 97.33 +/- 23.66). Significant between-group differences (iTBI vs. nTBI) were found for time to peak NSE (66.48 +/- 53.56 vs.8.11 +/- 11.58), S100B (43.30 +/- 51.41 vs. 8.21 +/- 8.29), and MBP (77.66 +/- 56.77 vs. 21.63 +/- 28.39). Time to peak concentrations were significantly correlated with outcome measures. Children with iTBI are at risk for poorer outcome. Acute measurement of NSE, S100B, and MBP serum concentrations may provide a quantitative predictor of outcome after TBI in young children. Outcome may be due to the mechanism of iTBI, cumulative effects of unreported TBI, and/or other unidentified risk factors.