OBJECTIVES: Describe the annual direct health care and indirect work loss costs for employees treated with antidepressants and compare them across patients with different treatment response. METHODS: We examined 1999-2003 data from a claims database of 1.2 million beneficiaries, from 7 large U.S. employers. Analysis was restricted to employees aged 18-64, with at least one diagnosis of major depressive disorder (ICD-9: 296.2x, 296.3x) and at least one prescription of selective serotonin or seratonin/norepinephrine reuptake inhibitor (SSRI/SNRI). Patients were classified as combination antidepressant therapy users, switchers, discontinuers, or monotherapy maintainers. Annual direct health care costs, including drug and medical costs (comprising inpatient, outpatient, and emergency visits), and indirect work loss costs (comprising absenteeism and disability) were calculated for the 12-month period following therapy initiation. Results were compared descriptively across treatment responses using t-tests and ANOVA analyses. RESULTS: Of the 3971 patients, 18.4% were on combination therapy, 19.7% switchers, 45.1% discontinuers, and 16.8% monotherapy maintainers. Patients on combination therapy had similar direct and indirect costs compared to switchers (all p>=0.08). The average direct and indirect costs for patients on combination therapy and switchers ($7986 and $2806 respectively) were higher than those for discontinuers ($6013 and $1680 respectively, all p<0.001) or maintainers ($5193 and $1467 respectively, all p<0.001). Compared to patients on combination therapy and switchers, maintainers had similar drug costs ($1980 vs. $2068, p=0.469). Compared to discontinuers, maintainers had higher drug costs ($1,980 vs. $1095, p<0.001), but lower medical ($3214 vs. $4918, p=0.002) and disability costs ($360 vs. $664, p=0.008). CONCLUSION: Patients on combination therapy or who switched monotherapy had higher average direct health care costs and indirect work loss costs than patients who discontinued or maintained therapy. Maintainers had higher drug costs but lower medical and disability costs compared to discontinuers.