Neural activation decreases cerebral deoxyhaemoglobin (HHbC) and increases oxyhaemoglobin concentration (O2HbC). In contrast, patients who present with restricted cerebral blood flow, such as those suffering from cerebral ischaemia or Alzheimer's disease, and during the course of ageing the converse occurs, in that HHbC increases and O2HbC decreases during neural activation. In the present study, we examined the interpretive implications of altered exercise-induced cerebral blood flow for cortical oxygenation in healthy subjects. Both O2HbC and HHbC (prefrontal cortex) were determined in 11 healthy men using near-infrared spectroscopy (NIRS). Middle cerebral artery mean blood velocity (MCA Vmean) was determined via transcranial Doppler ultrasonography. Measurements were performed during contralateral hand-grip exercise during suprasystolic bilateral thigh-cuff occlusion (Cuff+) and within 2 s of cuff release (Cuff–) for the acute manipulation of cerebral perfusion. During Cuff+, both MCA Vmean and O2HbC increased during exercise, whereas HHbC decreased. In contrast, the opposite occurred during the Cuff– manipulation. These findings highlight the inverse relationship between cerebral blood flow and cerebral oxygenation as determined by NIRS, which has interpretive implications for the kinetics underlying exercise-induced neural activation.