peer reviewed ; We analyzed gender differences in national Fatal OverDose (FOD) cases related to opiates and cocaine use between 1985 and 2011 (n=340). Methods Cross-examination of national data from law enforcement and drug use surveillance sources and of forensic evidence. Bi-variate and logistic regression analysis of male/female differences according to socio-demographics, forensic evidence and drug use trajectories. Results The burden of deaths caused by FOD on the general national mortality was higher for men (PMR/100 = 0.55) compared with women (PMR/100 = 0.34). Compared with their male peers, women were younger at the time of death (t=3.274; p=.001) and showed shorter drug use careers (t=2.228; p=.028). Heroin use was recorded more frequently in first drug offences of female victims [AOR=6.59 (95% CI 2.97–14.63)] and according to forensic evidence, psychotropic prescription drugs were detected to a higher degree in females [AOR=2.019 (95% CI 1.065–3.827)]. Conclusion The time window between the onset of illicit drug use and its fatal outcome revealed to be shorter for women versus men included in our study. Early intervention in female drug users, routine involvement of first line general health care providers and increased attention to poly and psychotropic prescription drugs’ use might contribute to prevent premature drug-related death and reduce gendered specificities.