The study was to establish effectiveness and side-effects of combined treatment with imipramine (IMI) and amantadine (AMA) of patients who present symptoms of treatment-resistant unipolar depression. Treatment-resistance was defined as the lack of response after two antidepressants from different groups, administered in adequate doses for at least 4 weeks each. The study was an open-label observation. The patients were randomised into two groups: those in the test group (n=25) were administered IMI for 6 weeks, and next, for the following 6 weeks, IMI was combined with AMA; the patients in the control group (n=25) were only treated with IMI for 12 weeks. Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) were carried out after O, 3, 6, 9, 12 weeks. The test group: Augmentation with AMA effected in a considerable decrease in the rating according to HDRS and BDI after 3 and 6 weeks. The control group: The treatment with IMI only did not change the rating according to HDRS and BDI. Comparison of the rating according to HDRS and BDI between the test group and the control group at the end of the study revealed a statistically significant difference. The side-effects (dry mouth and blood pressure drop) <lid not increase after AMA was added to IMI. Combined therapy with IMI and AMA can be effective and safety in treating drug-resistant unipolar depression.