Methods and systems are presented for determining regional blood oxygen saturation (rSO2) of a subject. Differential absorption values may be determined based on received first and second light signals corresponding to light attenuated by respective first and second regions of the subject. Reference absorption curves are received, each associated with an rSO2 value and containing expected absorption values. The differential absorption values are compared with the expected absorption values to determine a best fit reference absorption curve. An rSO2 value is determined based on the best fit reference absorption curve. An rSO2 value may also be determined based on a combination of two or more rSO2 estimates. The rSO2 estimates are determined based on two or more pairs of the differential absorption values. The differential absorption values are determined based on received first and second lights signals corresponding to three or more wavelengths of light.