OBJECTIVE: To describe the association between isoniazid preventive therapy (IPT) and mortality among individuals starting antiretroviral therapy (ART) in a workplace programme in South Africa where tuberculosis (TB) incidence is very high. METHODS: ART-naive individuals starting ART from January 2004 to December 2007 were followed for up to 12 months. Deaths were ascertained from clinic and human resource data. The association between IPT and mortality was assessed using Cox regression. RESULTS: A total of 3270 individuals were included (median age 45; 93% men; median baseline CD4 cell count 155 cells/μl (interquartile range 87-221); and 45% with WHO stage 3/4]. Nine hundred twenty-two (28%) individuals started IPT either prior to or within 3 months of starting ART. Individuals who started IPT tended to have less advanced HIV disease at ART initiation. Two hundred fifty-nine (7.9%) deaths were observed with overall mortality rate 8.9 per 100 person-years [95% confidence interval (CI) 7.9-10.6]. The unadjusted mortality rate was lower among those who received IPT compared with those who did not [3.7/100 vs. 11.1/100 person-years, respectively, hazard ratio 0.34 (95% CI 0.24-0.49)]; this association remained after adjustment for age, baseline CD4 cell count, baseline WHO stage, year of ART start, and individual company (hazard ratio 0.51, 95% CI 0.32-0.80). In sensitivity analyses restricted to those with no previous history of TB (n = 3036) or with no TB symptoms at ART initiation (n = 2251), IPT remained associated with reduced mortality [adjusted hazard ratios 0.51 (95% CI 0.32-0.81) and 0.48 (95% CI 0.24-0.96), respectively]. CONCLUSION: Mortality was lower among individuals receiving IPT with or prior to ART start. These results support routine use of IPT in conjunction with ART.