Hepatitis C virus (HCV) infection is now a global public health issue. However, the global burden of disease attributable to HCV infection is unknown. The objectives of this WHO informal consultation included the following: (1) defining a strategy to estimate the global burden of disease (GBD) associated with HCV infection in terms of morbidity and mortality, (2) describing the natural history of HCV infection in terms of morbidity and mortality, and (3) identifying areas for which more research is needed. The GBD project is an attempt to examine all causes of morbidity and mortality using an approach common to all conditions. The World Health Organization (WHO) already has estimated the burden of disease associated with hepatitis B virus (HBV) infection and is now about to conduct the same analysis for HCV infection. A review has been conducted to estimate the prevalence of HCV infection by age, gender, and region. These figures can be used to estimate incidence, although there are a number of areas of uncertainty. Combined with natural history parameters, incidence estimates could be used to estimate the future burden due to current infections. However, the present model is not validated and requires calibration before it can be used. A consensus was reached over the strategies to be used to (1) estimate the current burden due to past infections and (2) estimate the future burden due to current infections. Provisional expert consensus was reached over natural history parameters and cofactors that influence them. However, systematic literature reviews and meta-analysis are preferable for obtaining estimates to be included in models. Areas deserving future research include (1) obtaining a better estimate of HCV infection prevalence by age groups, (2) characterizing the various morbidity states associated with HCV infection and their disability weights, (3) understanding the long-term natural history of HCV infection beyond 20 years after infection, and (4) estimating the prevalence (and numbers of) of HCV infection among the drug-using population worldwide. A working group was created to address unmet needs and to assist the WHO in estimating the GBD associated with HCV infection.