A new method of measuring cerebral blood flow (CBF) in newborn infants by means of near infrared spectroscopy (CBFnirs) was compared with the i.v. 133Xe clearance technique (CBFxe). Forty CBFnirs measurements were obtained during 19 133Xe measurements in 16 infants; 79 other CBFnirs data sets were discarded because the assumptions for their use were not fulfilled. The test-retest variation of repeated near infrared-measurements during each 133Xe clearance was 17.5%. CBFnirs was closely related to CBFxe (r2 = 0.84, p less than 0.0001), with a slope of 0.75 (SEM = 0.064) and a intercept of 1.58 mL/100 g/min (SEM = 0.51). The difference between the measurements obtained by the two methods (CBFnirs-CBFxe) was negative in the high range of CBF, whereas the difference was close to zero in the low range. We conclude that CBF measured with near infrared spectroscopy was in good agreement with the CBF measured with the 133Xe method. The near infrared spectroscopy method has the advantage of being noninvasive, and it does not involve ionizing radiation. Because of methodologic constraints, however, it may underestimate CBF in the high range of flow, and it may have limitations of application in clinical research.