OBJECTIVE: Prone sleeping is a major risk factor for the sudden infant death syndrome and is associated with lower blood pressure and impaired arousability from sleep, both of which may be signs of cerebral hypoxia. However, the impact of sleep position on cerebral oxygenation during infancy remains unknown. We assessed the effects of sleeping position, sleep state, and postnatal age on cerebral oxygenation by measuring tissue oxygenation index (TOI) during the first 6 months of infancy. SUBJECTS AND METHODS: Seventeen healthy term infants (8 girls and 9 boys) were recruited as study participants. Infants were studied at ages 2 to 4 weeks, 2 to 3 months, and 5 to 6 months by use of daytime polysomnography, with additional measurements of blood pressure (Finometer, FMS Finometer Medical Systems, Amsterdam, Netherlands) and tissue oxygenation index (TOI) (NIRO 200 spectrophotometer, Hamamatsu Photonics KK, Tokyo, Japan). RESULTS: In infants who slept in the prone position, TOI was lower in both quiet sleep (QS) and active sleep (AS) at age 2 to 4 weeks and in QS at age 2 to 3 months (P <.05). TOI was lower in AS compared with QS in infants aged 2 to 4 weeks (P <.05). When the infants reached 5 to 6 months of age, TOI was greater in AS (P <.05), as there was a profound decrease in TOI during QS (P <.05) over this period. No relationship was identified between blood pressure and TOI at any age. CONCLUSIONS: In healthy infants cerebral oxygenation is reduced during sleep in the prone position. This reduction may underpin the reduced arousability from sleep exhibited by healthy infants who sleep prone, a finding that provides new insight into potential risks of prone sleeping and mechanisms of sudden infant death syndrome.