Depressive mixed states (DMS) are the most common form of mood disorders induced with interferon-alpha plus ribavirin therapy (IFN+RBV) for hepatitis C. The intensity of DMS is commonly mild but in some patients may be severe. Antidepressants are widely recognized as proper therapeutic option in alleviation of IFN+RBV-induced affective disorders. We report on two patients in whom severe DMS during the course of IFN+RBV therapy developed and standard treatment was found ineffective. Both patients were assessed with Bipolar Depression Rating Scale after emerging DMS and during the course of psychotropic treatment. Patient A was 29-year old music teacher and had never been psychiatrically treated. He suffered from marked dysphoria, disturbances of attention and conduct, insomnia, asthenia and low mood from first month of peg-IFN-alpha-2a+RBV therapy. Treatment with carbamazepine, then with gabapentin plus sulpiride was ineffective. Significant reduction of psychopathology was seen with concomitant use of quetiapine (500 mg a day) and gabapentin (1600 mg a day). Patient B was 53–year old businessman previously treated due to three mild episodes of major depression. DMS symptoms seriously influenced his functioning and developed from first month of peg-IFN-alpha-2a+RBV. Quetiapine monotherapy (400 mg a day) remarkably reduced DMS symptoms. The patient achieved sustained viral response. Psychopharmacological treatment in both cases did not influence aminotranferase levels and both patients completed antiviral therapy. Conclusion. In hepatitis C patients with severe depressive mixed states induced with IFN+RBV therapy administration of mood stabilizers may be considered as safe and effective.