To determine the burden and impact of immune reconstitution disease (IRD) associated with tuberculosis (TB) among patients initiating antiretroviral treatment (ART) in sub-Saharan Africa. Retrospective analysis of a study cohort enrolled over 3 years within a community-based ART service in South Africa. Patients receiving treatment for TB at the time ART was initiated (n = 160) were studied. Cases of TB-associated IRD during the first 4 months of ART were ascertained. The median baseline CD4 cell count was 68 cells/microl [interquartile range (IQR), 29-133 cells/microl) and ART was initiated after a median of 105 days (IQR, 61-164 days) from TB diagnosis. Although IRD was diagnosed in just 12% (n = 19) of patients overall, IRD developed in 32% (n = 12) of those who started ART within 2 months of TB diagnosis. Pulmonary involvement was observed in 84% (n = 16) and intra-abdominal manifestations were also common (37%). Overall, 4% (n = 7) of the cohort required secondary level health-care for IRD and two (1%) patients died. In multivariate analysis, risk of IRD was strongly associated with early ART initiation and low baseline CD4 cell count. Of patients with CD4 counts 120 days of TB diagnosis were 100%, 33%, 14%, 7% and 0%, respectively. The risk of TB-associated IRD in this setting is very high for those with low baseline CD4 cell counts initiating ART early in the course of antituberculosis treatment. However, most cases were self-limiting; overall secondary health-care utilization and mortality risk from IRD were low.