- Background: This article reviews the published clinical data on treatment-resistant schizophrenic and schizoaffective patients managed with combinations of “atypical” antipsychotic medication. Method: A computerized MEDLINE literature search covering an 18-year period (1985–2003) was conducted. All pertinent papers on the subject of the use of combination “atypical” antipsychotic medication in the management of treatment-resistant schizophrenia and schizoaffective disorder were obtained with subsequent analysis and discussion of the retrieved data. Results: The search identified 29 case reports and case series reports (172 patients) and one double-blind placebo-controlled trial (28 patients) describing the use of combination “atypical” antipsychotic medication (clozapine–risperidone; clozapine–sulpiride; clozapine–olanzapine; clozapine–quetiapine; olanzapine–sulpiride; olanzapine–quetiapine; risperidone–olanzapine; risperidone–quetiapine) in the treatment of resistant schizophrenic and schizoaffective patients. An overview of results suggests that the combinations were beneficial in the described patients with reduction of positive symptoms and occasionally negative symptoms. Significant adverse effects, while rare, were reported in a few cases and did not appear to different in nature from those managed on monotherapeutic regimens. Conclusion: Combinations of “atypical” antipsychotic medications are well tolerated and may be effective in the management of treatment refractory schizophrenia and schizoaffective disorder. However, further double-blind placebo-controlled trials are required in order to test and confirm these observations.