The aim of this study was to determine the prevalence and identify risk factors associated with the spread of hepatitis B and C in the rural areas of the upper Sindh Province, Pakistan. Included in this cross-sectional survey were 873 subjects belonging to 174 families residing in Jarwar, a small town of upper Sindh. A study using a systematic random sampling method was undertaken. One questionnaire per household was filled out and blood samples collected for hepatitis B surface antigen (HBsAg), hepatitis B core antibody total (HBcAb), and hepatitis C antibody (anti-HCV). HBsAg was reactive in 44 (5%), HBcAb in 494 (56.6%) and anti-HCV in 294 (33.7%). In the case control study, independent risk factors for exposure to hepatitis B were male sex, age greater than 16 years, absence of vaccination, previous history of jaundice, and family history of liver disease (adjusted odds ratios 1.4, 2.1, 1.7, 1.8 and 1.8, respectively). Independent risk factors for hepatitis C were age greater than 16 years, previous dental procedures, history of liver disease, lack of vaccination, and 10 or more injections in a year (adjusted odds ratios 3.7, 2.1, 2.4, 1.8 and 2.9, respectively). There was indication of intrafamilial and household clustering: for hepatitis C, parent to child p = 0.001, sibling-to-sibling p = 0.046; for hepatitis B, spouse-to-spouse p = 0.052 and parent to child p = 0.001. In conclusion, there is high exposure to hepatitis B and C in upper Sindh. There is a need to educate people about hepatitis B vaccination and iatrogenic factors responsible for transmission. The study suggests the possibility of intrafamilial spread of these viruses.