Little is known about hepatitis B virus (HBV) infection among patients with chronic hepatitis C virus (HCV) infection in the United States. We prospectively enrolled 1,257 patients with chronic HCV infection from two medical centers in New York City. A total of 61.5% (95% confidence interval, 58.8%-64.2%) had evidence of prior exposure to HBV (hepatitis B core antibody-positive), whereas 5.8% (95% confidence interval, 4.5%-7.1%) had dual infection with HBV (hepatitis B surface antigen-positive). Multivariable logistic regression analysis identified age <40 years, Asian race, injection drug use, and a greater number of lifetime sexual partners as independent risk factors for HBV-HCV dual infection. Liver biopsy results in 26 HBV-HCV-infected and 658 HCV-monoinfected patients showed that stage 3 or 4 fibrosis was significantly more common in those with HBV-HCV dual infection (84.6% versus 29.9%; P < 0.001). Patients infected with HBV and HCV had significantly lower median HCV RNA levels (1.3 versus 4.5 x 10(6) copies/mL; P < 0.001) and were less likely to have HCV RNA levels ≥5 x 10(6) copies/mL (12.3% versus 45.4%; P < 0.001) than those who had HCV monoinfection. All five patients with HBV-HCV dual infection who had undetectable HBV DNA levels had HCV RNA levels ≥5 x 10(6) copies/mL. Conclusion: American patients with chronic HCV infection should be tested for HBV, especially younger patients, Asians, injection drug users, and those with an increased number of lifetime sexual partners. The presence of severe liver disease and HBV-HCV viral interactions in patients with dual infection necessitates careful but aggressive clinical management, although the optimal strategy remains to be determined.