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Background Multi-substance use is accompanied by increased morbidity and mortality and responsible for a large number of emergency department (ED) consultations. To improve the treatment for this vulnerable group of patients, it is important to quantify and break down in detail the ED resources used during the ED treatment of multi-substance users. Methods This retrospective single centre case-control study included all ED consultations of multi-substance users over a three-year study period at a university hospital in Switzerland. Resource consumption of these patients was compared to an age-matched control group of non-multi-substance users. Results The analysis includes 867 ED consultations of multi-substance users compared to 4,335 age-matched controls (5:1). Multi-substance users needed more total resources (median tax points [medical currency] (IQR): 762 (459-1226) vs. 462 (196-833), p<0.001), especially physician, radiology, and laboratory resources. This difference persisted in multivariable analysis (geometric mean ratio (GMR) 1.2, 95% CI: 1.1-1.3, p = 0.001) adjusted for sociodemographic parameters, consultation characteristics, and patient comorbidity; the GMR was highest in ED laboratory and radiology resource consumption. Among multi-substance user, indirect and non-drug-related consultations had higher ED resource consumption compared to drug-related consultations. Furthermore, leading discipline as well as urgency were predictors of ED resource consumption. Moreover, multi-substance users had more revisits (55.2% vs. 24.9%, p<0.001) as well as longer ED and in-hospital stays (both: GMR 1.2, 95% CI: 1.1-1.3, p<0.001). Conclusion ED consultations of multi-substance users are expensive and resource intensive. Multi-substance users visited the ED more often and stayed longer at the ED and in-hospital. The findings of our study underline the importance of this patient group. Additional efforts should be made to improve their ED care. Special interventions