Background and aim: One source of error with near-infrared spectroscopy (NIRS) is the assumption that the measured tissue is optically homogeneous. This is not always the case. Our aim is to assess the impact of tissue homogeneity (TH) on the precision of NIRS measurements in neonates. Methods: On 36 term and 27 preterm neonates at least five 1-min measurements are performed on each subject using the OxiplexTS. The sensor position is slightly changed before each measurement while assessing TH. The precision for cerebral tissue oxygenation saturation (StO2) and total hemoglobin concentration (tHb) are calculated by repeated measures analysis of variance. Results: The mean StO2 is not significantly different between term and preterm infants. The mean tHb is significantly lower in preterm infants (p < 0.01). With increasing TH, the precision of StO2 increase from 5.6 to 4.6% for preterm and from 11.0 to 2.0% for term infants; the precision of tHb increases from 10.1 to 7.5μM for preterm and from 16.4 to 3.5μM for term infants. The precision for StO2 is higher in term than in preterm infants. The precision for tHb shows no significant difference between the two groups. Conclusions: The precision of NIRS measurements correlates with tissue homogeneity.