This study aimed to understand and appraise the approaches taken to handle the complexities of a multisystem disease in published decision-analytic model-based economic evaluations of treatments for SLE. A systematic review was conducted to identify all published model-based economic evaluations of treatments for SLE. Treatments that were considered for inclusion comprised antimalarial agents, immunosuppressive therapies, and biologics including rituximab and belimumab. Medline and Embase were searched electronically from inception until September 2018. Titles and abstracts were screened against the inclusion criteria by two reviewers; agreement between reviewers was calculated according to Cohen’s κ. Predefined data extraction tables were used to extract the key features, structural assumptions and data sources of input parameters from each economic evaluation. The completeness of reporting for the methods of each economic evaluation was appraised according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Six decision-analytic model-based economic evaluations were identified. The studies included azathioprine (n=4), mycophenolate mofetil (n=3), cyclophosphamide (n=2) and belimumab (n=1) as relevant comparator treatments; no economic evaluation estimated the relative cost-effectiveness of rituximab. Six items of the CHEERS statement were reported incompletely across the sample: target population, choice of comparators, measurement and valuation of preference-based outcomes, estimation of resource use and costs, choice of model, and the characterisation of heterogeneity. Complexity in the diagnosis, management and progression of disease can make decision-analytic model-based economic evaluations of treatments for SLE a challenge to undertake. The findings from this study can be used to improve the relevance of model-based economic evaluations in SLE and as an agenda for research to inform future health technology assessment and decision-making.