Insulin resistance (IR) is associated with poor cerebrovascular health and an increased risk for dementia. Little is known about the unique effect of IR on both micro and macrovessel flow particularly in midlife when interventions against dementia may be most effective. We examined the effect of IR as indexed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) on cerebral blood flow in both macrovessels and microvessels utilizing magnetic resonance imaging (MRI) among cognitively healthy middle-aged individuals. We hypothesized that higher HOMA-IR would be negatively associated with blood flow in macrovessels supplying the brain, which in turn would be associated with lower cortical perfusion at the level of the microvasculature. 120 cognitively healthy middle-aged adults (57±5 yrs, cognitive health determined by mini-mental state examination (MMSE) and immediate and delayed memory testing, Rey Auditory Verbal Learning Test (RAVLT)) underwent fasting blood draw, phase Contrast (PC) MRI and arterial spin labeling (ASL) perfusion MRI. HOMA-IR was calculated from fasting insulin and glucose measures (HOMA-IR = [Insulin] (uIU/mL) x [Glucose] (mg/dL) / 405). Mean flow (ml/min) was measured in the internal carotid arteries (ICA, right and left) and the basilar artery (BA). CBF blood flow was then calculated as the sum of bilateral ICA and BA flow. HOMA-IR was regressed against CBF and perfusion using linear regression controlling for several co-morbid risk factors, as well as interactions between IR and CBF on perfusion. All subjects had normal cognitive function (MMSE = 29.4±0.7, immediate memory RAVLT = 10.4±1.6, Delayed Memory RAVLT = 10.3±2.7). Higher HOMA-IR was associated with lower CBF (F[1,122] = 4.76, p = 0.031), particularly within the ICAs (right ICA, F[1,122] = 4.87, p = 0.029, left ICA, F[1,122] = 5.65, p = 0.019). Voxel-wise analyses of ASL data revealed a main effect of HOMA-IR, highlighting hypoperfusion in the right anterior cingulate (t = 3.5, p = 0.0001) and the left middle frontal gyrus (t = 3.7, p = 0.0001). Further, high ICA flow was predictive of higher cortical perfusion in the right superior frontal gyrus only in individuals with low HOMA-IR (t = 3.8, p = 0.0001); This relationship was not found in individuals with high HOMA-IR. Our findings provide novel evidence for an uncoupling of macrovessel flow and microvessel perfusion among individuals with higher IR and emphasize the importance of normal insulin function on cerebrovascular health in midlife. Furthermore, the observed relationships have implications for interventions aimed at promoting normal insulin and cerebrovascular function in midlife to attenuate risk for pathological aging.