BACKGROUND: There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz (EFV) compared to nevirapine (NVP) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large, urban HIV clinic in Uganda. METHODS: Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multivariable logistic regression model), stratifying by baseline CD4(+) T-cell count. Adjustment for time-updated CD4(+) T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses. RESULTS: ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (sd 9) and a median baseline CD4(+) T-cell count of 117 cells/mm(3) (IQR 43-182). Overall, 60% (n=3,484) were initiated on NVP and 40% (n=2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4(+) T-cell count textless100 cells/mm(3) (HR 2.05 [95% CI 1.29, 3.27]; P=0.003), but not at higher CD4(+) T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P=0.428). These estimates were robust to all sensitivity analyses. CONCLUSIONS: There was a higher incidence of TB in patients with baseline CD4(+) T-cell counts textless100 cells/mm(3) initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.