Background: We investigated the association between social determinants and a broad selection of drug-related deaths in a general population. Methods: We conducted a follow-up of an 11% random sample of working-age Finnish residents for 1996-2007 linked with an oversampling of deaths and population registration data on social characteristics. We defined total drug-related deaths as those from psychoactive substance use disorders and drug-induced poisonings (drug induced deaths) as well as drug-related accidents, homicides, illnesses, and suicides. Results: The number of drug-related deaths was three times that of drug-induced deaths. We found the highest hazard ratios (HRs) for total drug-related mortality for long-term unemployment (4.9; 95% confidence interval [CI], 4.3-5.6), short-term unemployment (3.9; 95% CI, 3.5-4.4), and retirement (5.8; 95% CI, 5.1-6.8). The HRs were highest for mortality related to psychoactive substance use disorders and lowest for mortality related to drug-related suicides. The differences were large for both sexes. Conclusions: Drug-related mortality was associated with social disadvantage; however, the strength of the association varied by drug-related cause of death. Primary and secondary prevention of drug use should particularly target disadvantaged groups.