The neurobiological basis of cancer-related post-traumatic stress disorder (PTSD) has never been studied. We investigated brain structural alterations and the longitudinal courses in patients with cancer-related PTSD. Baseline scans using magnetic resonance imaging were performed in 14 cancer survivors with PTSD, 100 without PTSD, and 70 healthy subjects. Follow-up scans were performed 2 years later in 76 cancer survivors (PTSD, n=9; non-PTSD, n=67). Using voxel-based morphometry, the gray matter volume (GMV) of the cancer survivors with PTSD was compared with the GMVs of those without PTSD and of the healthy subjects. The effects of the interactions between the diagnosis and the timing of the GMV measurements were examined. The GMV of the right orbitofrontal cortex (OFC) was significantly smaller in cancer survivors with PTSD than in those without PTSD or healthy subjects. The interaction between the diagnosis and the timing of the right OFC's GMV measurement was not significant. The OFC, which is thought to be involved in the extinction of fear conditioning and the retrieval of emotional memory, might play an important role in the pathophysiology of PTSD. Moreover, the OFC's GMV may remain constant after the development of cancer-related PTSD.