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Objective: Antipsychotic polypharmacy is widespread in schizophrenia treatment, and it has been observed to become more widespread over the years. However, the benefits of antipsychotic polypharmacy in schizophrenia treatment are controversial. The present study aims to investigate the relationship between antipsychotic polypharmacy and the quality of life. Methods: Ninety two patients who met DSM-IV criteria for schizophrenia were divided into monotherapy (MT) and polypharmacy (PP) groups with respect to their medications. The quality of life was assessed using the Quality of Life Scale (QLS), the severities of symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale, and the side effects of antipsychotics were assessed using the UKU Side Effect Rating Scale. Results: Total QLS scores in the PP group were significantly lower than those in the MP group. The total antipsychotic doses and the frequencies of the side effects including sedation, dystonia, erectile and ejaculation dysfunction were detected to be higher in the PP group in comparison to the MP group. Total QLS scores were found to be significantly subject to the direct influence of total PANSS negative scores. Conclusion: Poorer quality of life, more severe negative symptoms and more frequent antipsychotic side effects were observed in patients who were receiving antipsychotic polypharmacy, in comparison to patients who were receiving antipsychotic monotherapy. The presence of negative symptoms, and consequently lack of improvement in symptoms may lead clinicians to prefer antipsychotic polypharmacy. However, antipsychotic polypharmacy does not bring sufficient improvement in symptoms and quality of life, whereas it leads to higher antipsychotic doses and increased side effects. [Anadolu Psikiyatri Derg 2016; 17(6.000): 433-441]