peer reviewed ; To describe trends in the national prevalence of fatal overdose (FOD) cases related to opiates and cocaine use between 1985 and 2011. To analyse male/female differences in FOD victims according to various time periods. Methods. A triangulation approach was chosen to cross-examining data from national law enforcement sources, the national drug use surveillance system (RELIS) and of forensic and toxicological evidence. Data have been stratified according to 3 time periods covering each 9 successive years in order to increase the visibility of long term variations and trends. Statistical analysis of male/female differences according to socio-demographic and forensic data as well as drug use trajectories was performed. Results. National FOD prevalence has been decreasing from the beginning of this century to reach a historically low rate of 1.71 cases/100,000 inhabitants in 2011. The burden of deaths caused by FOD on the general national mortality showed to be higher for men compared with women. Furthermore, the pathways towards a FOD revealed to be different for male and female victims referred to various aspects including age of decedents, criminal records, drug use trajectories, drug use patterns and the involvement of psychotropic prescription drugs. Conclusions. The time window for intervention between the onset of drug use and its potential fatal outcome might be shorter for women compared with men. Further research should address dynamics between socio-economic status of victims and various cultural components to assess their possible impact on drug overdose induced mortality. Early intervention in female drug users and increased attention to poly and psychotropic prescription drugs use should be considered in health promotion programmes and relevant research outcomes routinely provided to first line general health care providers to accelerate access to appropriate treatment if required and eventually contribute to prevent premature death and reduce gender inequalities.