AIM: To study factors associated with loss of hepatitis B surface antigen (HBsAg) in patients co-infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV).METHODS: We retrospectively reviewed the medical records of 5681 patients followed up at two New York City HIV clinics from January 1999 to May 2007. Clinical and laboratory parameters including baseline and follow-up HIV viral loads, CD4 cell counts, alanine transaminase levels, demographics, presence of hepatitis C infection, and treatment with highly active antiretroviral therapy dually active against both HIV and HBV infection, were analyzed to determine factors associated with loss of HBsAg.RESULTS: Three hundred and fifty five patients (355/5681, 6.84%) were co-infected with HIV and HBV and were evaluated. Of these, 226 patients with more than 12 mo follow-up were included in further analysis to determine factors associated with loss of HBsAg in the long-term follow-up. In the univariate analysis, baseline CD4 cell count was associated with loss of HBsAg ( P = 0.052).Cox regression analysis revealed that loss of HBsAg was associated with baseline CD4 cell count > 500 cells/mm3 ( P = 0.016, odds ratio: 76.174, 95% confidence interval: 2.233-2598.481).CONCLUSION: Our study showed an interesting association of loss of HBsAg in HIV-HBV co-infected patients with higher CD4 cell count, suggesting that T-cell cytolytic activity against HBV may still be effective in clearing HBV infection.