Background: In individuals co-infected with HIV and hepatitis B virus (HBV), widespread tenofovir (TDF)-containing antiretroviral therapy (ART) has led to substantial decreases in HBV-DNA and HIV-RNA detection. However, the link between viral replication, liver fibrosis, and mortality remains unclear. Methods: 300 HIV-HBV co-infected individuals undergoing ART were prospectively followed. Virological and clinical data were obtained at baseline and every 6-12 months. We quantified the association between HBV-DNA, HIV-RNA, and liver fibrosis with risk of all-cause mortality using a joint longitudinal-survival model. Viral detection, viral loads, and time-averaged cumulative viral loads of HIV and HBV were modeled as three separate exposures. Results:During a median 10.5 years (IQR=4.0-14.6), the proportion undergoing TDF-containing ART (baseline=18.7%, end of follow-up=79.1%) and with undetectable HBV-DNA (baseline=36.7%, end of follow-up=94.8%) substantially increased. HIV-RNA was mostly undetectable during follow-up (76.6%). 42 participants died (incidence rate=1.30/100person-years, 95%CI=0.96-1.76). The leading causes of death were non-AIDS/non-liver-related malignancies (28.6%), followed by liver-related (16.7%), AIDS-related (16.7%), and other (16.7%). All-cause mortality was associated with HBV-DNA viral load (adjusted-HR per log10IU/mL=1.41, 95%CI=1.04-1.93, p=0.03) or time-averaged cumulative HBV-DNA (adjusted-HR per log10IU-years=1.37, 95%CI=1.03-1.83, p=0.03), but not undetectable HBV-DNA (adjusted-HR=0.30, 95%CI=0.08-1.09, p=0.08). Advanced liver fibrosis at baseline was also associated with increased mortality rates (adjusted-HR=2.35, 95%CI=1.16-4.76, p=0.02). No significant association between HIV-RNA replication and mortality was observed. Conclusions: Concurrent and historical HBV replication and liver fibrosis are important drivers of all-cause mortality in largely TDF-treated HIV-HBV co-infected individuals, despite one-fifth of deaths being liver-related. HBV-DNA and liver fibrosis remain important prognostic indicators for this patient population.