Objective: In an exploratory study, authors compared patients with late-life major depression (MDD) and age-matched control subjects to examine sex differences in frontal and orbito-frontal (OFC) regional brain volumes. Methods: The study sample comprised 41 patients with MDD and 41 controls. Subjects underwent comprehensive neuropsychiatric examinations and magnetic resonance imaging (MRI) scans. Corrected frontal and OFC gray-matter volumes were compared among men and women in both groups. Results: The depression group had lower MMSE scores, greater severity of medical burden, apathy, psychomotor retardation, and poor health-related quality of life than the controls. Men in both groups had a greater severity of medical burden, apathy, and psychomotor retardation than women. The depression group bad smaller OFC total and gray-matter volumes than the controls after matching for age. Men bad smaller frontal-matter volumes than women in both groups. The diagnosis X sex interaction in brain regional volumes was observed only after controlling for medical burden. Conclusions: Sex differences in brain neuroanatomy may be important in the pathophysiology of geriatric depression. Men may be susceptible to atrophy in frontal subregions. Medical burden may contribute to the diagnosis X sex interaction in brain regional volumes.