IntroductionThe HIV Prevention Trials Network (HPTN) 074 study demonstrated a positive effect of an integrated systems navigation and psychosocial counseling intervention on HIV treatment initiation, viral suppression, medication assisted treatment (MAT) enrollment, and risk of death among people who inject drugs (PWID). In this sub-study, we analyzed the incidence, causes, and predictors of death among HIV-infected and uninfected participants.MethodsThe HPTN 074 randomized clinical trial was conducted in Indonesia, Ukraine, and Vietnam. HIV-infected PWID with unsuppressed viral load (indexes) were recruited together with at least one of their HIV-negative injection partners. Indexes were randomized in a 1:3 ratio to the intervention or standard of care.ResultsThe trial enrolled 502 index and 806 partner participants. Overall, 13% (66/502) of indexes and 3% (19/806) of partners died during follow-up (crude mortality rates 10.4 [95% CI 8.1–13.3] and 2.1 [1.3–3.3], respectively). These mortality rates were for indexes nearly 30 times and for partners 6 times higher than expected in a population of the same country, age, and gender (standardized mortality ratios 30.7 [23.7–39.0] and 5.8 [3.5–9.1], respectively). HIV-related causes, including a recent CD4 < 200 cells/μL, accounted for 50% of deaths among indexes. Among partners, medical conditions were the most common cause of death (47%). In the multivariable Cox model, the mortality among indexes was associated with sex (male versus female aHR = 4.2 [1.5–17.9]), CD4 count (≥ 200 versus < 200 cells/μL aHR = 0.3 [0.2–0.5]), depression (moderate-to-severe versus no/mild aHR = 2.6 [1.2–5.0]) and study arm (intervention versus control aHR = 0.4 [0.2–0.9]). Among partners, the study arm of the index remained the only significant predictor (intervention versus control aHR = 0.2 [0.0–0.9]) while controlling for the effect of MAT (never versus ever receiving MAT aHR = 2.4 [0.9–7.4]).ConclusionsThe results confirm that both HIV-infected and uninfected PWID remain at a starkly elevated risk of death compared to general population. Mortality related to HIV and other causes can be significantly reduced by scaling-up ART and MAT. Access to these life-saving treatments can be effectively improved by flexible integrated interventions, such as the one developed and tested in HPTN 074.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12879-023-08201-3.