Triple infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis D virus (HDV) is rare. The influence of HDV infection on the responses to highly active antiretroviral therapy and hepatic complications in patients with HBV-HIV coinfection remains uncertain. Twenty-six HDV-infected case patients and 78 HDV-uninfected matched control subjects were identified between 1 January 1995 and 30 June 2003. Clinical and immunologic outcomes were noted, and HBV and HIV loads and genotypic resistance of HBV to lamivudine were determined. Case patients had a higher rate of injection drug use (7.7% vs. 1.3%; P=.05) and lower serum levels of HBV DNA (median level, 4.04 vs. 5.75 log10 copies/mL; P=.07) than control subjects. During a median observation period of 54.7 months, HDV infection did not have an adverse impact on clinical, virological, or immunologic responses to highly active antiretroviral therapy. However, case patients had higher rates of hepatitis flares (57.7% vs. 23.1%; P=.002), hyperbilirubinemia (34.6% vs. 14.1%; P=.04), liver cirrhosis (26.9% vs. 5.1%; P=.009), hepatic decompensation (23.1% vs. 5.1%; P=.007), and death (adjusted hazard ratio, 5.41; 95% confidence interval, 1.39-23.85; P=.02), although these patients had a lower risk of genotypic resistance to lamivudine (0% vs. 57.1%; P=.003). HDV infection did not affect clinical, virological, or immunologic responses to highly active antiretroviral therapy in patients with HBV-HIV coinfection. HDV infection increased risk of hepatitis flares, liver cirrhosis, hepatic decompensation, and death in patients with HBV-HIV coinfection.