Olfactory reference syndrome (ORS) is characterized by a preoccupation with the belief that one releases an offensive odor that is not perceived by and the patient feels is burdensome to others. Although ORS was first described in the 1800s, the first systematic description in the literature was a case series in 1971 by Pryse-Phillips. Notably, ORS is not categorized in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5); ORS is associated with schizophrenia, delusional disorder, obsessive-compulsive disorder, or mood disorders. Here, we present a patient with major depressive disorder (MDD) and ORS who was successfully treated with vortioxetine. To our knowledge, this is the first report of vortioxetine improved ORS in an MDD patient. Written informed consent was obtained from the patient for publication of this case report.