Background: While delays in cognitive development are detectable during early development in Down syndrome, the neuropsychological and biomedical underpinnings of cognitive skill acquisition in this population remain poorly understood. Method: To explore this issue, 38 infants with Down syndrome [mean chronological age = 9.65 months; SD = 3.64] completed the Bayley Scales of Infant Development-III and a set of laboratory tasks that measured sustained attention (duration of visual attention during a 1-min object exploration task), attention shifting (mean latency to shift attention on an alternating object presentation task) and visual short-term memory (dishabituation to a novel object on a change preference task). Results: Latency to shift attention was negatively associated with Bayley Cognitive Scale raw scores, even when controlling for the effects of chronological age, r (33) = -0.41, P = 0.02. In addition, prematurity status was associated with latency to shift attention. Conclusions: Early attention shifting may be an important factor that facilitates overall cognitive skill acquisition in infants with Down syndrome, and premature birth may be a risk factor for difficulties on this dimension.