Existential suffering may contribute to treatment-resistant depression. The "VITA" treatment model was designed for such patients with long-standing depression accompanied by existential and/or religious concerns. This naturalistic effectiveness study compared the VITA model (n = 50) with a "treatment as usual" comparison group (TAU; n = 50) of patients with treatment-resistant depression and cluster c comorbidity. The TAU patients were matched on several characteristics with the VITA patients. The VITA model included existential, dynamic, narrative and affect-focused components. The VITA group had significantly greater improvement on symptom distress and relational problems during treatment and from pre-treatment to 1-year follow-up. Patients in the VITA, at follow-up, were more likely to be employed and less likely be using psychotropic medications.