OBJECTIVE: To systematically review and analyse data from cohorts of people who inject drugs (PWID) to improve existing estimates of non-AIDS mortality used to calculate mortality among PWID in the Spectrum Estimates and Projection Package. DESIGN: Systematic review and meta-analysis. METHODS: We conducted an update of an earlier systematic review of mortality among PWID, searching specifically for studies providing data on non-AIDS-related deaths. Random-effects meta-analyses were performed to derive pooled estimates of non-AIDS crude mortality rates across cohorts disaggregated by sex, HIV status and periods in and out of opioid substitution therapy (OST). Within each cohort, ratios of non-AIDS CMRs were calculated and then pooled across studies for the following paired sub-groups: HIV-negative versus HIV-positive PWID; male versus female PWID; periods in OST versus out of OST. For each analysis, pooled estimates by country income group and by geographic region were also calculated. RESULTS: Thirty-seven eligible studies from high-income countries and five from low and middle-income countries were found. Non-AIDS mortality was significantly higher in low and middle-income countries [2.74 per 100 person-years; 95% confidence interval (CI) 1.76-3.72] than in high-income countries (1.56 per 100 person-years; 95% CI 1.38-1.74). Non-AIDS CMRs were 1.34 times greater among men than women (95% CI 1.14-1.57; N = 19 studies); 1.50 times greater among HIV-positive than HIV-negative PWID (95% CI 1.15, 1.96; N = 16 studies); and more than three times greater during periods out of OST than for periods on OST (N = 7 studies). CONCLUSIONS: A comprehensive response to injecting drug must include efforts to reduce the high levels of non-AIDS mortality among PWID. Due to limitations of currently available data, including substantial heterogeneity between studies, estimates of non-AIDS mortality specific to geographic regions, country income level, or the availability of OST should be interpreted with caution.