BACKGROUND: Uncertainty exists regarding the prevalence and clinical features associated with the practice of polypharmacy in bipolar disorder (BD), warranting a systematic review on the matter. METHODS: Three authors independently searched major electronic databases from inception till September 2015. Articles were included that reported either qualitative or quantitative data about the prevalence and clinical features associated with polypharmacy in adult cases of BD. RESULTS: The operative definitions of polypharmacy adopted across varying studies varied, with concomitant use of two or more psychotropic medications or use of four or more psychotropic medications at once being the most common and the most reliable, respectively. Regardless of type or current mood episode polarity of BD, prevalence rates up to 85% and 36% were found using the most permissive (two or more medications at once) and the most conservative (four or more) operative definitions for polypharmacy, respectively. Point prevalence prescription rates of one or more antidepressant or antipsychotic as part of a polypharmacy regimen occurred in up to 45% or 80% of the cases, respectively, according to the most permissive definition of polypharmacy. In contrast, lithium prescription rates ranged from 13% to 33% in BD patients receiving polypharmacy according to conservative and permissive definitions, possibly suggesting a reduced need for augmentation of combination strategies for those cases of BD with a favorable lifetime lithium response and/or long-lasting treatment as well as less likelihood of lithium response over the time most severe cases possibly exposed to a more complex polypharmacy overall. LIMITATIONS: "Apples and oranges" bias; publication bias for most recently introduced compounds. CONCLUSION: Polypharmacy is common among people with BD across varying type and mood episode phases of illness. Special population, including BD patients at high risk of familial load for suicidal behavior, solicit further research as well as the plausible "protective" role of lithium toward polypharmacy in BD. The PROSPERO registration number is CRD42014015084.