OBJECTIVE: Sleep patterns in children with Autism Spectrum Disorder (ASD) appear to diverge from typical development in the second or third year of life. Little is known, however, about the occurrence of sleep problems in infants who later develop ASD and possible impacts on early brain development. In a longitudinal neuroimaging study of infants at familial high (HR) or low risk (LR) for ASD, parent-reported sleep-onset problems were examined in relation to subcortical brain volumes in the first two years of life. METHODS: 432 infants were included across 3 groups: HR who developed ASD (n=71), HR who did not (n=234), and LR (n=127). Sleep-onset problem scores (derived from an infant temperament measure) were evaluated in relation to longitudinal high-resolution T1 & T2 structural imaging data acquired at 6, 12, and 24 months of age. RESULTS: Sleep-onset problems were more common at 6–12 months for infants who later developed ASD. Infant sleep-onset problems were related to hippocampal volume trajectories from 6–24 months only for those HR infants who developed ASD. Brain-sleep relationships were specific to the hippocampus; no significant relationships were found with volume trajectories of other subcortical structures examined (amygdala, caudate, globus pallidus, putamen, or thalamus). CONCLUSIONS: These findings provide initial evidence that sleep-onset problems in the first year of life precede ASD diagnosis and are associated with altered neurodevelopmental trajectories in HR siblings who go on to develop ASD. If replicated, these findings could provide new insights into a potential role of sleep difficulties in the development of ASD.