OBJECTIVES: Prescribing of more than one antidepressant drug (poly-pharmacy) is not clinically substantiated in literature and such a practice could contribute to additional side-effects. Antidepressant drugs are prescribed to patients diagnosed with psychiatric and non-psychiatric medical conditions. The objective of this study was to determine the patient demographics, non-demographic factors and physician characteristics associated with prescribing poly-pharmacy antidepressants in both psychiatric and non-psychiatric cases. METHODS: The 2000-2009 National Ambulatory Medical Care Survey database was accessed for medical records of patients who were prescribed the antidepressant drugs. The medical records were sorted into psychiatric and non-psychiatric categories. A logistic regression analysis helped determine the patient demographic, non-demographic and physician characteristics associated with prescribing poly-pharmacy antidepressant drugs. RESULTS: For patients diagnosed with psychiatric illnesses: Patient demographic factors of age (p<0.0001), gender (p=0.0087), race/ethnicity (p=0.0091), method of payment (p=0.0283), non-demographic factors of diagnosis (p<0.0001), and number of medical condition diagnosed (p<0.0001, OR=1.259, CI=1.125-1.408) were significantly associated with prescribing poly-pharmacy antidepressant drugs. Among the physician related factors, physician specialty (p<0.0001) and the region of practice (South) (p=0.0475) were significantly associated with prescribing poly-pharmacy antidepressant drugs. For patients diagnosed with non-psychiatric illnesses: Patients’ age (p<0.0001), method of payment (p=0.0444), and among the non-demographic characteristics, the number of medical conditions diagnosed (p=0.0246, OR=1.16, CI=1.019-1.320), and patients diagnosed with circulatory system disease (p=0.0111) were significantly associated with the practice of poly-pharmacy. Of the physician related factors physicians classified as owners of non-solo practice (p=0.0306) were significantly associated with prescribing poly-pharmacy antidepressant drugs.  CONCLUSIONS: The fact that more than 40% of poly-pharmacy antidepressant drugs was prescribed to patients diagnosed with non-psychiatric illnesses, and the significant association between the poly-pharmacy antidepressants prescribed and the number of medical conditions diagnosed in both psychiatric and non-psychiatric patients lends to further investigation as to the reasonableness of such practices.