OBJECTIVES: Bipolar disorder (BD) is one of the leading causes of disability secondary to mental/behavior disorders worldwide. We aimed to evaluate the economic burden imposed by BD over employability; work performance and health related quality-of-life (HRQoL) of patients in the United States (US). METHODS: We conducted a comprehensive search in Medline and EMBASE from 2006 to 2016 for studies addressing the following aspects: cost-of-illness (direct and indirect costs and impact of specific pharmacological treatments), impact over employability and work productivity, HRQoL (over course of illness and during specific pharmacological treatments). RESULTS: We included 26 studies evaluating cost-of-illness. Annual societal costs per BD patient varied from $1,904 to $33,090, with production losses making up to 20%-94% of costs. Overall direct healthcare costs ranged from $8,000-$14,000 purchasing power parities. Total annual health care costs were higher for BD patients than for those without ($12,764 vs $3,140). Improved adherence to medication was related to lower medical costs in BD (1-point increment in MPR reduced $123-$439 mental health expenditures in manic/mixed symptoms patients receiving antipsychotics). Fifteen studies addressed impact of BD over employability and work productivity. Around 40%-60% of BD patients were employed, with higher employment rates during early phases of disease compared to later stages. Mean annual absence costs (sick leave, short/long-term disability, and workers' compensation) were significantly higher for BD employers when compared with those without the disease ($1,995 vs $885). Results from 11 studies showed that HRQOL is impaired in BD patients compared with healthy individuals and with patients diagnosed with other chronic psychiatric and medical conditions. BD pharmacological and non-pharmacological treatments have a positive effect on HRQOL. CONCLUSIONS: When compared with other populations, BD patients imposed higher medical costs for payers; however, treatment adherence was associated with reduced health expenditures. Both employability and work productivity were negatively affected by the disease, as was HRQoL.