Background: The combination of multiple agents including lithium, mood stabilizers and antipsychotics, represents the most commonly strategy in bipolar disorder treatment. Lack of response, breakthrough episodes during adequate maintenance treatment, functional impairment, including re-hospitalization, suicide attempts and intolerance of medication are considered clinical inclusion criteria for treatment resistance in bipolar disorder. In bipolar disorder, Clozapine as mono-therapy or in combination treatment, remains as a efficacious second line agent, with few clinical data available, mainly including short observational periods, small samples and uncontrolled trials. Methods: We analyze retrospectively clinical data about five female bipolar refractory patients who were under combined treatment including atypical antipsychotics. Due to this combined first line treatment resistance, Clozapine was indicated as an add-on agent. Equivalent analysis periods were established for each patient, previous and under Clozapine use. These periods extends from 8 months to 5 years and 2 months. Results: Clozapine average daily dose was 260 mgs. No adverse effects were noticed. Total hospitalization days decrease from 979 days to 118 days andsu icide attempts decrease from 14 ep isodes in pre Clozap ine period to 1 episode in the Clozapine treatment period. No re-hospitalization neither self harm attempts with Clozapine add on treatment were reported in 3 patients. Conclusion: Clozapine efficacy, in treatment resistance bipolar patients, should be considered as a second line option in combination therapy with insufficient response. Therapeutic benefits of Clozapine may include potential decrease of self harm conduct in bipolar patients as in schizophrenia and schizoaffective disorder.