BACKGROUND: Despite widespread use in HIV and hepatitis B virus (HBV) infection, the effectiveness of tenofovir (TDF) has not been studied extensively outside of small cohorts of coinfected patients with HBV-HIV. We examined the effect of prior lamivudine (3TC) treatment and other factors on HBV DNA suppression with TDF in a multisite clinical cohort of coinfected patients. METHODS: We studied all patients enrolled in the Centers for AIDS Research Network of Integrated Clinical Systems cohort from 1996 to 2011 who had chronic HBV and HIV infection, initiated a TDF-based regimen continued for ≥ 3 months and had on-treatment HBV DNA measurements. We used Kaplan-Meier curves and Cox-proportional hazards to estimate time to suppression (HBV DNA level <200 IU/mL or <1000 copies/mL) by selected covariates. RESULTS: Among 397 coinfected patients on TDF, 91% were also on emtricitabine or 3TC concurrently, 92% of those tested were hepatitis B e antigen positive, 196 (49%) had prior 3TC exposure; 192 (48%) achieved HBV DNA suppression over a median of 28 months (interquartile range: 13-71). Median time to HBV DNA suppression was 17 months for those who were 3TC-naive and 50 months for those who were 3TC exposed. After controlling for other factors, prior 3TC exposure, baseline HBV DNA level >10,000 IU/mL, and lower nadir CD4 count were independently associated with decreased likelihood of HBV DNA suppression on TDF. CONCLUSIONS: These results emphasize the role of prior 3TC exposure and immune response on delayed HBV suppression on TDF.