peer reviewed ; Background: To investigate social and economic inequalities in fatal overdose cases related to opioid and cocaine use, recorded in Luxembourg between 1994 and 2011. Methods: Cross-examination of national data from law enforcement and drug use surveillance sources and of forensic evidence in a nested case–control study design. Overdose cases were individually matched with four controls, when available, according to sex, year of birth, drug administration route and duration of drug use. 272 cases vs 1056 controls were analysed. Conditional logistic regression analysis was performed to assess the respective impact of a series of socioeconomic variables. Results: Being professionally active [OR = 0.66 (95% CI 0.45–0.99)], reporting salary as main legal income source [OR = 0.42 (95% CI 0.26–0.67)] and education attainment higher than primary school [OR = 0.50 (95% CI 0.34–0.73)] revealed to be protective factors, whereas the professional status of the father or legal guardian of victims was not significantly associated to fatal overdoses. Conclusions: Socioeconomic inequalities in drug users impact on the occurrence of fatal overdoses. Compared to their peers, users of illicit drugs with lower socioeconomic profiles show increased odds of dying from overdose. However, actual and self-referred socioeconomic characteristics of drug users, such as educational attainment and employment, may have a greater predictive value of overdose mortality than the parental socioeconomic status. Education, vocational training and socio-professional reintegration should be part of drug-related mortality prevention policies.