OBJECTIVES: Innovative antidepressants such as SSRIs and SNRIs have been widely adopted. However, the differences in patient antidepressant adherence and associated health care spending across patient factors and antidepressant choice needed further research. This study was trying to understand how patient factors and antidepressant choice influenced medication adherence and associated health care expenditure. METHODS: A retrospective cross-sectional study was conducted using the 2000-2007 Medical Expenditure Panel Survey (MEPS) database. A multiple OLS regression was used to examine MDD patient’s antidepressant adherence measured by proportional days covered (PDC). A two-part model was implemented to study the impact of MDD patient factors and antidepressant choice on associated health care expenditure. RESULTS: Linear regression models indicated that patient gender, ethnicity and health insurance status were associated with differential levels of antidepressant adherence and associated health expenditure. Hispanic ethnicity was associated with decreased antidepressant adherence compared to non-Hispanic white (β=12.53, p<0.05) and other ethnicities (β=28.27, p<0.01). Patient who were covered by public insurance had better PDC compared to uninsured patients (β=16.23, p<0.05). Patient who were covered by private insurance spent more on MDD-specific drug compared to uninsured patients (β=0.36, p<0.05). Higher antidepressant adherence was associated with higher MDD-specific drug expenditure (β=0.03, p<0.01). Use of innovative antidepressants such as SSRIs and SNRIs was associated with an increase in MDD-specific drug expenditure. CONCLUSIONS: Differences in antidepressant adherence and health care spending across patient factors could have important policy implications for drug formularies and health disparities. Solutions for gaps between optimal and suboptimal health care for patient mental health caused by systematic differences in sociological factors need to be well tailored. We need policy makers to be engaged in designing effective policy interventions to improve patient medication adherence, and to fund cost-effectiveness studies to improve patient outcomes and in turn, reduce associated health expenditure.