INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.