Objectives Neonatal-onset organic acidemias (OAs) account for 80% of neonatal intensive care unit (NICU) admissions due to inborn errors of metabolism. The aim of this study is to analyze clinical features and follow-up of neonates diagnosed with OAs in a metabolic referral center, focusing on perinatal characteristics and the impact of first the metabolic crisis on long-term outcome. Methods Perinatal features, clinical and laboratory characteristics on admission and follow-up of 108 neonates diagnosed with OAs were retrospectively analyzed. Global developmental delay, abnormal electroencephalogram (EEG) or brain magnetic resonance imaging (MRI), chronic complications, and overall mortality. Associations between clinical findings on admission and outcome measures were evaluated. Results Most prevalent OA was maple syrup urine disease (MSUD) (34.3%). Neonates with methylmalonic acidemia (MMA) had significantly lower birth weight (p Conclusions Metabolic acidosis and hyperammonemia are emerging predictors of poor outcome and mortality. Based on a large number of infants from a single center, survival in neonatal-onset OA has increased over the course of 30 years, but long-term complications and neurodevelopmental results remain similar. While prompt onset of more effective treatment may improve survival, newer treatment modalities are urgently needed for prevention and treatment of chronic complications.