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Abstract Background Treating patients with acute poisoning by substances of abuse in a primary care emergency clinic has previously been shown to be a safe strategy. We conducted an economic evaluation of this strategy compared to hospital treatment, which is the usual strategy. Methods Assuming equal health outcomes, we conducted a cost-minimization analysis. We constructed a representative opioid overdose patient based on a cohort of 359 patients treated for opioid overdose at the Oslo Accident and Emergency Outpatient Clinic (OAEOC) from 1.10.2011 to 30.9.2012. Using a health care system perspective, we estimated the expected resources used on the representative patient in primary care based on data from the observed OAEOC cohort and on information from key informants at the OAEOC. A likely course of treatment of the same patient in a hospital setting was established from information from key informants on provider procedures at Drammen Hospital, as were estimates of hospital use of resources. We calculated expected costs for both settings. Given that the treatments usually last for less than one day, we used undiscounted cost values. Results The estimated per patient cost in primary care was 121 EUR (2018 EUR 1.00 = NOK 9.5962), comprising 97 EUR on personnel costs and 24 EUR on treatment costs. In the hospital setting, the corresponding cost was 612 EUR, comprising 186 EUR on personnel costs, 183 EUR on treatment costs, and 243 EUR associated with intensive care unit admission. The point estimate of the cost difference per patient was 491 EUR, with a low-difference scenario estimated at 264 EUR and a high-difference scenario at 771 EUR. Conclusions Compared to hospital treatment, treating patients with opioid overdose in a primary care setting costs substantially less. Our findings are probably generalizable to poisoning with other substances of abuse. Implementing elements of the OAEOC procedure in primary care emergency clinics and in hospital emergency departments could improve the use of health care resources.