Despite its importance as the leading cause of vascular dementia, the primary pathogenic mechanisms in subcortical ischemic vascular dementia (SIVD) have remained elusive. Due to the lack of approved therapeutic agents for SIVD, there is a pressing need to identify novel therapeutic targets. Comparative lipidomic analyses of SIVD and mixed dementia (i.e. SIVD and Alzheimer’s disease, MixD) may also confer new insights pertaining to the possible interaction between neurodegenerative and vascular mechanisms in the pathogenesis of dementia. Liquid chromatography coupled to mass spectrometry was used to comprehensively analyze the lipidomes of white and grey matter from the temporal cortex of non-demented controls, SIVD and MixD subjects. Detailed molecular profiles highlighted the pathological relevance of grey matter sphingolipid fatty acyl chain heterogeneity in dementia. In addition, the levels of sulfatides and lysobisphosphatidic acids were progressively increased in the temporal cortex grey matter from control to SIVD to MixD. White matter phospholipid profiles indicated possible adaptive mechanisms (i.e. increased unsaturation) to chronic ischemia in SIVD and elevated membrane degradation in MixD.