OBJECTIVES: To describe the methods of cost-of-illness (COI) studies on multimorbidity; and to summarize the economic outcomes of multimorbidity. METHODS:  A systematic search for COI studies of multimorbidity published in English from 2000 to 2016 was performed. Inclusion criteria: peer-reviewed cross-sectional, cohort and modeling COI studies of multimorbidity; exclusion criteria: studies focusing on the index disease. Data extracted for each eligible study included definition, measure, prevalence of multimorbidity; number of included health conditions; age range of sample; methodology of COI; proportion of multimorbidity costs and average costs per capita. The adapted British Medical Journal Checklist was used to assess the study quality. Costs were converted to 2016USD using the 2016 exchange rate for each currency, with adjustments over time based on the Consumer Price Inflation. RESULTS:  26 articles were included, of which, the definition used in the 14 studies that clearly defined multimorbidity was limited to a simple count of 2 or more conditions. Methodology used to derive costs differed markedly among the studies. Average annual costs per patient of multimorbidity ranged from $49-$252,313; the ratios of multimorbidity over non-multimorbidity costs ranged from 2-16. The highest costs ($252,313) were found in a study of American children. Using a cut-off of 3 or more conditions, average costs were 7%-85% higher than 2 or more conditions within 14 available studies. Among 10 studies providing a breakdown on costs, the largest proportion for multimorbidity was spent on inpatient (95%) or medicines (64%) costs in non-societal perspective studies, while on social care cost from societal perspective (56%). CONCLUSIONS:  COI studies of multimorbidity are highly heterogeneous. Multimorbidity was associated with considerable economic burden even in children. Costs of different definitions of multimorbidity were limited by the data available. Standardized methods are required for improving accuracy, enhancing interpretation and facilitating comparisons between studies from different perspectives.