Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is associated with considerable liver disease morbidity and mortality. Emerging HIV epidemics in areas of high HBV endemicity such as Asia are expanding the population with HIV/HBV coinfection. Limited randomized trial data exist to support current guidelines for HBV combination therapy in HIV/HBV coinfection. The objective of this prospective randomized clinical trial was to compare the strategy of HBV monotherapy with lamivudine (LAM) or tenofovir disoproxil fumarate (TDF) versus HBV combination therapy with LAM/TDF in antiretroviral-naïve HIV/HBV-coinfected subjects in Thailand. Thirty-six HIV/HBV-coinfected subjects initiating highly active antiretroviral therapy (HAART) were randomized to either LAM (arm 1), TDF (arm 2), or LAM/TDF (arm 3) as HBV-active drugs within HAART. At week 48, time-weighted area under the curve analysis revealed that the median HBV DNA reduction from baseline was 4.07 log(10) c/mL in arm 1, 4.57 log(10) c/mL in arm 2, and 4.73 log(10) c/mL in arm 3 (P = 0.70). HBV DNA suppressed to <3 log(10) c/mL in 46% in arm 1, 92% in arm 2, and 91% in arm 3 (P = 0.013, intent-to-treat analysis). HBV-resistant changes were detected in two subjects, both in arm 1. Hepatitis B e antigen (HBeAg) loss was observed in 33% of HBeAg-positive subjects, and 8% experienced hepatitis B surface antigen loss. Hepatic flare was observed in 25% of subjects. CONCLUSION: LAM monotherapy resulted in a greater proportion of subjects with HBV DNA >3 log(10) c/mL at week 48 and in early resistance development. This study confirms current treatment guidelines that recommend a TDF-based regimen as the treatment of choice for HIV/HBV coinfection, but does not demonstrate any advantage of HBV combination therapy in this short-term setting.