HCV is spread primarily by direct contact with human blood. Transmission through blood transfusions that are not screened for HCV infection, through the reuse of inadequately sterilized needles, syringes or other medical equipment, or through needle-sharing among drug-users, is well documented. Sexual and perinatal transmission may also occur, although less frequently. Other modes of transmission such as social, cultural, and behavioural practices using percutaneous procedures (e.g. ear and body piercing, circumcision, tattooing) can occur if inadequately sterilized equipment is used. HCV is not spread by sneezing, hugging, coughing, food or water, sharing eating utensils, or casual contact.

In both developed and developing countries, high risk groups include injecting drug users, recipients of unscreened blood, haemophiliacs, dialysis patients and persons with multiple sex partners who engage in unprotected sex.

In developed countries, it is estimated that 90% of persons with chronic HCV infection are current and former injecting drug users and those with a history of transfusion of unscreened blood or blood products.

In many developing countries, where unscreened blood and blood products are still being used, the major means of transmission are unsterilized injection equipment and unscreened blood transfusions. In addition, people who use traditional scarification and circumcision practices are at risk if they use or re-use unsterilized tools.