A historical cohort study was carried out in Rome to examine overall and cause-specific mortality among intravenous drug users (IVDUs). A total of 4200 IVDUs (3411 men and 789 women) enrolled in methadone treatment centers between 1980 and 1988 were studied. There were 239 deaths during the follow-up period. The overall SMR was 10.10 in the entire cohort (95% confidence interval, 8.86-11.47), 9.30 in males and 18.07 in females. A large excess of mortality in both sexes was found for infectious, circulatory, respiratory, and digestive diseases as well as for violence, overdose, AIDS, and unknown or ill-defined causes. Tumors and suicide were excessive only in males. Deaths due to drug overdose, violence or trauma, and cirrhosis accounted for 63.6%, AIDS for 7.1%, endocarditis and other bacterial infections for 7.1%, and neoplasms for 3.8% of total mortality. These findings document serious health consequences of drug abuse in Italy.