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Although liver disease (especially hepatitis C) is common, its impact on mortality is low in active injectors. Because opioid substitution therapy (OST) reduces the risk of death from directly drug related causes, we hypothesised that the proportion of liver\u2010related deaths would increase in subjects receiving OST. We investigated liver\u2010related mortality in a cohort of injecting opioid users attending a needle exchange program (NEP) in a Swedish city in relation to OST exposure.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Design and Methods<\/jats:title><jats:p><jats:italic>Participants enrolled in the NEP between 1987 and 2011 with available national identity numbers, and registered use of opioids, were included. Linkage based on national identity numbers was performed with national registers for death, emigration and prescription of OST. Participants were categorised as non\u2010OST recipients until the registered date of first OST prescription, and hence as OST recipients. Hazard ratios were calculated by Cox regression for overall and liver\u2010related mortality in relation to OST, with OST as a time\u2010dependent variable<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Among 4494 NEP participants, 1488 opioid users were identified; 711\/1488 had been prescribed OST. During a follow\u2010up period of 15\u2009546 person\u2010years 368 deaths occurred. Sixteen deaths were caused by liver disease; 10 of these occurred in OST recipients. The risk of liver\u2010related death was significantly increased in OST receiving participants (hazard ratio 3.08, 95% confidence interval [1.09, 8.68], P\u2009=\u20090.03)<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:italic>Liver related mortality among opioid users was significantly elevated in OST recipients, showing the long\u2010term importance of chronic liver disease in this population.<\/jats:italic> [Jerkeman A, H\u00e5kansson A, Rylance R, Wagner P, Alanko Blom\u00e9 M, Bj\u00f6rkman P. 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