Changes in cerebral blood flow are an essential feature of Alzheimer’s disease and have been linked to apolipoprotein E-genotype and cerebral amyloid-deposition. These factors could be interdependent or influence cerebral blood flow via different mechanisms. We examined apolipoprotein E-genotype, amyloid beta-deposition, and cerebral blood flow in amnestic mild cognitive impairment using pseudo-continuous arterial spin labeling MRI in 27 cognitively normal elderly and 16 amnestic mild cognitive impairment participants. Subjects underwent Pittsburgh Compound B (PiB) positron emission tomography and apolipoprotein E-genotyping. Global cerebral blood flow was lower in apolipoprotein E ɛ4-allele carriers (apolipoprotein E4+) than in apolipoprotein E4− across all subjects (including cognitively normal participants) and within the group of cognitively normal elderly. Global cerebral blood flow was lower in subjects with mild cognitive impairment compared with cognitively normal. Subjects with elevated cerebral amyloid-deposition (PiB+) showed a trend for lower global cerebral blood flow. Apolipoprotein E-status exerted the strongest effect on global cerebral blood flow. Regional analysis indicated that local cerebral blood flow reductions were more widespread for the contrasts apolipoprotein E4+ versus apolipoprotein E4− compared with the contrasts PiB+ versus PiB− or mild cognitive impairment versus cognitively normal. These findings suggest that apolipoprotein E-genotype exerts its impact on cerebral blood flow at least partly independently from amyloid beta-deposition, suggesting that apolipoprotein E also contributes to cerebral blood flow changes outside the context of Alzheimer’s disease.