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Previous studies documented that near-infrared spectroscopy values were affected by factors related to optical path length, such as hemoglobin concentration, the differential path length factor, skull thickness (t-skull), and the area of the cerebrospinal fluid layer (a-CSFL). Lately, the NIRO-100 (Hamamatsu Photonics, Hamamatsu, Japan) has provided a tissue oxygen index (TOI) that theoretically is not supposed to be affected by optical path length. Therefore, the authors hypothesized that TOI is not influenced by the above-described individual factors.Cardiac surgical or neurosurgical 103 patients (65 men and 39 women; aged 63 ± 14 yr) were studied. TOI and regional cerebral oxygen saturation (rSO2) (INVOS 4100; Somanetics, Troy, MI) were measured sequentially on patients in a resting state. The t-skull and a-CSFL were calculated using computed tomographic image slices of the head corresponding with the position of near-infrared spectroscopy sensors. The effects of these two factors, hemoglobin concentration and mean arterial pressure, on TOI and rSO2 values were evaluated by linear regression analysis.Simple linear regression analysis showed that mean arterial pressure (r = 0.27, P = 0.008), t-skull (r = 0.22, P = 0.034), a-CSFL (0.26, P = 0.012), and hemoglobin concentration (r = 0.42, P < 0.0001) were significant determinants of rSO2. Multiple linear regression analysis showed that hemoglobin concentration (r = 0.34, P < 0.001), a-CSFL (r = −0.252, P = 0.012), and t-skull (r = 0.22, P = 0.037) were significant determinants of rSO2. On the other hand, simple and multiple linear regression analysis showed that there was no significant determinant of TOI.rSO2 values were affected by hemoglobin concentration, a-CSFL, and t-skull, but TOI values were not affected by individual factors.