Cabin air in airplanes can be contaminated with engine oil contaminants. These contaminations may contain organophosphates (OPs) which are known neurotoxins to brain white matter. However, it is currently unknown if brain white matter in aircrew is affected. We investigated whether we could objectify cognitive complaints in aircrew and whether we could find a neurobiological substrate for their complaints. After medical ethical approval from the local institutional review board, informed consent was obtained from 12 aircrew (2 females, on average aged 44.4 years, 8,130 flying hours) with cognitive complaints and 11 well matched control subjects (2 females, 43.4 years, 233 flying hours). Depressive symptoms and self-reported cognitive symptoms were assessed, in addition to a neuropsychological test battery. State of the art Magnetic Resonance Imaging (MRI) techniques were administered that assess structural and functional changes, with a focus on white matter integrity. In aircrew we found significantly more self-reported cognitive complaints and depressive symptoms, and a higher number of tests scored in the impaired range compared to the control group. We observed small clusters in the brain in which white matter microstructure was affected. Also, we observed higher cerebral perfusion values in the left occipital cortex, and reduced brain activation on a functional MRI executive function task. The extent of cognitive impairment was strongly associated with white matter integrity, but extent of estimated number of flight hours was not associated with cognitive impairment nor with reductions in white matter microstructure. Defects in brain white matter microstructure and cerebral perfusion are potential neurobiological substrates for cognitive impairments and mood deficits reported in aircrew.