Infection with the hepatitis C virus (HCV) is known to increase the risk of death from severe liver disease and, because HCV status is strongly associated with a history of injecting drug use, the effect of a key disease progression cofactor, infection with human immunodeficiency virus (HIV), is of interest. We examined all-cause, liver-related and drug-related mortality and excess risk of death from these causes in a large cohort of HCV-monoinfected and HIV-coinfected persons in Scotland. The study population consisted of 20,163 persons confirmed to be infected with hepatitis C through laboratory testing in Scotland between 1991 and 2005. Records with sufficient identifiers were linked to the General Register Office for Scotland death register to retrieve associated mortality data, and were further linked to a national database of HIV-positive individuals to determine coinfection status. A total of 1715 HCV monoinfected and 305 HIV coinfected persons died of any cause during the follow-up period (mean of 5.4 and 6.4 years, respectively). Significant excess mortality was observed in both HCV monoinfected and HIV coinfected populations from liver-related underlying causes (standardised mortality ratios of 25, 95% CI = 23-27; and 37, 95% CI = 26-52 for the two groups, respectively) and drug-related causes (25, 95% CI = 23-27; 39, 95% CI = 28-53. The risk of death from hepatocellular carcinoma, alcoholic or non-alcoholic liver disease, or from a drug-related cause, was greatly increased compared with the general Scottish population, with the highest standardised mortality ratio observed for hepatocellular carcinoma in the monoinfected group (70, 95% CI = 57-85). This study has revealed considerable excess mortality from liver- and drug-related causes in the Scottish HCV-diagnosed population; these data are crucial to inform on the clinical management, and projected future public health burden, of HCV infection.