Background To understand the relationship between blood pressure changes during standing up and clinical outcome, cerebral oxygenation needs to be measured, which may be performed using near-infrared spectroscopy (NIRS). However, the role of potential determinants of NIRS-derived orthostatic cerebral oxygenation, i.e., age, sex, type of postural change (i.e., standing up from sitting versus supine position), blood pressure (BP) and baroreflex sensitivity (BRS) is still unknown and needed to better interpret findings from studies using orthostatic NIRS measurements. Methods 34 younger (median age 25 years, inter quartile range (IQR) 22–45) and 31 older adults (median age 77 years, IQR 72–81) underwent BP, BRS and NIRS measurements during standing up from sitting and supine position. Linear regression models were used to assess the potential determinant role of age, sex, type of postural change, BP and BRS in orthostatic cerebral oxygenation drop and recovery. Orthostatic cerebral oxygenation test-retest reliability was assessed using intra class correlations. Results Younger age, male sex and standing up from supine compared to sitting position were positively associated with cerebral oxygenation drop; older age and standing up from sitting compared to supine position were associated with higher cerebral oxygenation recovery. Test-retest reliability was highest (ICC textgreater 0.83) during standing up from supine position. Conclusion Based on the findings of this study, age, sex and type of postural change are significant determinants of NIRS-derived orthostatic cerebral oxygenation and should be taken into account in the interpretation of NIRS measurements. In the design of new studies, standing up from supine position is preferable (higher reliability) over standing up from sitting position.