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Increases in deaths due to liver-related disease (LRD) among HIV-infected individuals have been reported although the influence of combination antiretroviral therapy (cART) on LRD is controversial.To determine changes over time in the death rate from LRD and if longer exposure to cART was associated with an increased death rate from LRD in 10 937 patients from EuroSIDA, an observational longitudinal cohort study.A total of 184 (1.7%) died from LRD during 52 236 person-years of follow-up (PYFU). The death rate from LRD declined from 6.9 per 1000 PYFU before 1995 [95% confidence interval (CI), 3.9–9.9] to 2.6 at/after 2004 (95% CI, 1.6–4.0). When the current CD4 cell count and other factors were taken into account, there was a 13% increase in the death rate from LRD per year (95% CI, 5–20%, P = 0.0008). In patients who had started cART, there was a 12% increase in the death rate from LRD per additional year exposure to cART (95% CI, 4–20%, P = 0.022) after adjustment for current CD4 cell count and other factors.Death rates from LRD appeared to decrease across Europe. However after adjustment for the current CD4 cell count, and therefore increases in CD4 cell counts in patients taking cART, there was a significant increase over time in death rates from LRD. In patients with similar CD4 cell counts, longer exposure to cART was associated with an increased death rate from LRD. This may be due to direct liver toxicity of antiretrovirals, progression of liver disease due to hepatitis B virus or hepatitis C virus over time as patients survive longer, or some other factor.