Objective Late‐life depression has been associated with risk for cerebrovascular pathology, as demonstrated in neuroimaging studies of older depressed patients, as well as mood disorder following cerebrovascular accidents. However, more research is needed on neuroanatomical changes in late‐life depression, where there has been no clearly documented link to brain injury. Such studies should examine morphological changes in medium and small sized vessels that supply the cortical gray and white matter. Methods The present study used a non‐specific histological Nissl staining and a more vessel‐specific immunolabeling with endothelial marker von Willebrand Factor (vWF) to estimate density and size of blood vessel segments in the orbitofrontal cortex of 16 older subjects with major depressive disorder (MDD) and 9 non‐psychiatric comparison subjects. Results The density of Nissl‐stained vessel segments and of segments with perivascular spaces was higher in subjects with MDD than in comparison subjects in gray (GM) and white matter (WM). In GM, the density of vWF‐immunoreactive segments with cross‐sectional areas greater than 800 µm2 was higher in MDD. In WM, only the density of vWF‐immunoreactive segments with patent perivascular spaces and diameters larger than 60 µm was higher in subjects with MDD. Also in the WM, only subjects with late‐onset MDD presented a significantly higher density of vWF‐positive segments than comparison subjects. Conclusions In older subjects with MDD, there appear to be morphological changes that increase visibility of medium‐sized vessel segments with some labeling techniques, and this increased visibility may be related to increased patency of perivascular spaces around arterioles. Copyright © 2012 John Wiley & Sons, Ltd.