In HBV/HIV-co-infected individuals, the course of hepatitis B is aggravated, leading to higher morbidity and mortality rates. Increasing evidence suggests an important role for hepatitis B surface antigen (HBsAg) quantification in monitoring treatment efficacy in HBV monoinfection. However, data concerning any HBsAg decline during treatment of HBV/HIV coinfection are limited. Fifty-one HBV/HIV-co-infected patients were retrospectively followed for a mean of 43 months (median 2 years, interquartile range 2 years). Baseline and on-treatment parameters were associated with longitudinal HBsAg levels. At baseline, serum HBsAg levels were comparable between patients on antiretroviral therapy (ART; n=43) and patients without (n=8). Longitudinally, HBsAg decreased in ART patients (-0.20±0.09 log(10) IU/mL/y), but slightly increased in subjects without therapy (0.22±0.26 log(10) IU/mL/y; p<0.001). In 58% of the ART subjects an HBsAg decline >10% was seen during the initial 24 mo. They showed higher baseline CD4 counts (401±42 versus 265±50 cells/μL, p=0.03), and had significantly higher CD4 counts at the last follow-up compared to patients without a decline (506±39 versus 310±51 cells/μL, p=0.01). A significant correlation was found between HBsAg decline from baseline to the last follow-up and the absolute increase of CD4 cells (r=0.44, p=0.003), as well the last CD4 count (r=0.41, p=0.006). This association was strongest in patients with complete suppression of HBV-DNA and HIV-RNA at the last follow-up visit. The highest HBsAg decline (-1.63±0.32 versus -0.43±0.24 log(10) IU/mL, p=0.001), and yearly HBsAg decline (-0.47±0.13 versus -0.19±0.12 log(10) IU/mL, p=0.03), were found in patients with CD4 increases >100 cells/μL at the last follow-up (n=21, 49%). Four cases of HBsAg loss were observed (8%). HBsAg declines steadily in >50% of HBV/HIV patients on ART. Long-term follow-up of HBV/HIV-co-infected patients is needed to identify distinct HBsAg patterns. Increasing CD4 counts indicating the restoration of immune competence in HBV/HIV-co-infected patients is associated with a stronger HBsAg decline.