Abstract Background People who inject drugs (PWID) experience many health problems which result in a heavy economic and public health burden. To tackle this issue, France opened two drug consumption rooms (DCRs) in Paris and Strasbourg in 2016. This study assessed their long-term health benefits, costs and cost-effectiveness. Methods We developed a model to simulate two fictive cohorts for each city ( n =2,997 in Paris and n =2,971 in Strasbourg) i) PWID attending a DCR over the period 2016-2026, ii) PWID attending no DCR. The model accounted for HIV and HCV infections, skin abscesses and related infective endocarditis, drug overdoses and emergency department visits. We estimated the number of health events and associated costs over 2016-2026, the lifetime number of quality-adjusted life-years (QALYs) and costs, and the incremental cost-effectiveness ratio (ICER). Results The numbers of abscesses and associated infective endocarditis, drug overdoses, and emergency department visits decreased significantly in PWID attending DCRs (-77%, -69%, and -65%, respectively) but the impact on HIV and HCV infections was modest (-11% and -6%, respectively). This resulted in savings of €6.6 (Paris) and €5.8 (Strasbourg) millions of medical costs. The ICER of DRCs was €30,600/QALY (Paris) and €9,200/QALY (Strasbourg). In scenario analysis where drug consumption spaces are implemented inside existing harm reduction structures, these ICERs decreased to €21,400/QALY and €2,500/QALY, respectively. Conclusions Our findings show that DCRs are highly effective and efficient to prevent harms in PWID in France, and advocate extending this intervention to other cities by adding drug consumption spaces inside existing harm reduction centers.