Premature, very-low-birth-weight (VLBW; ≤1500 g) and low-birth-weight (LBW; 1500-2499 g) infants are at increased risk for severe neurological disability. 25-50% of the 63,000 VLBW infants born annually in the USA have major longterm cognitive or neurobehavioral deficits in which cerebral hypoxia plays an important role. At present, no technology is capable of noninvasive, accurate monitoring of cerebral oxygenation in newborns. We proposed to use an optoacoustic technique for noninvasive cerebral hypoxia monitoring by probing the superior sagittal sinus (SSS). Recently, we developed and built a medical grade, multi-wavelength, near-infrared optoacoustic system suitable for neonatal applications. We designed and built an adjustable patient interface for neonates with VLBW, LBW, and normal weight (NBW) that provides single or continuous measurements of the SSS blood oxygenation in both the reflection and transmission modes. We performed pilot clinical tests of the system in VLBW, LBW, and NBW hemodynamically stable infants admitted to the neonatal intensive care unit. The system was capable of detecting SSS signals through the open anterior and posterior fontanelles and through the skull and allowed for monitoring of the SSS blood oxygenation in both modes. To the best of our knowledge this paper reports for the first time detection of optoacoustic signals from human cerebral blood vessels in both the transmission mode and the reflection mode. Analysis of the signals allows for noninvasive measurement of cerebral venous blood oxygenation in newborns in both modes. The transmission mode can be used for accurate measurement of the total hemoglobin concentration as well. The method and system proposed in this study can be used for optoacoustic human brain imaging, tomography, and mapping.