AIMS: To estimate all-cause mortality rate and to assess predictors of all-cause mortality among injection drug users (IDUs) in Thai Nguyen province, Vietnam between 2005 and 2007. DESIGN: Prospective cohort study. SETTING: Community-dwelling IDUs were enrolled and followed at 3-month intervals for up to 2 years. PARTICIPANTS: A total of 894 male IDUs (median age of 32 years, 22.8% HIV-positive, all having injected opioids). MEASUREMENTS: Deaths were confirmed by family members and by reviewing government records. Marginal Cox proportional hazards models for clustered data were constructed to determine the independent predictors of all-cause mortality, using both fixed baseline measurements and time-dependent repeated measurements. FINDINGS: During 710.1 person-years of follow-up, 45 (5.0%) drug injectors died. The causes of deaths were AIDS-related (14 cases, 31%), drug overdose (12, 27%), suicide (three, 7%), traffic accident (three, 7%), violence (two, 4%), pneumonia (two, 4%), non-traffic accident (one, 2%) and unknown causes (eight, 18%). The all-cause mortality rate was 6.3% (95% CI = 4.6-8.5) per 100 person-years. The standardized mortality ratio was 13.4. The HIV incidence rate was 5.2 (95% CI = 3.5-7.6) per 100 person-years. In multi-factorial analysis, HIV infection [hazard ratio (HR) = 3.5, 95% CI = 1.9-6.3] and previous diagnosis of tuberculosis (HR = 10.0, 95% CI = 4.1-24.3) were associated significantly with increased hazard of death. CONCLUSIONS: The all-cause, age- and sex-standardized mortality among Vietnamese IDUs is 13-fold higher than the general population and substantially higher than IDUs studied in developed countries. Effective prevention and control of HIV infection and tuberculosis are needed urgently.