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Background: CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates. Methods: HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003–2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to <200 cells/mm3 were referred for antiretroviral therapy (ART) and were analytically censored. Results: 1106 ARV naïve adults were enrolled. Their median age was 30 years and male to female ratio was 1∶5. Median baseline CD4 count was 490 cells/mm3 (IQR 351–675). The overall mean decline in CD4 count was 61 cells/mm3 per annum. Adjusting for age, gender, baseline hemoglobin, smoking and alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of <10,000 (N = 314), 10,001–100,000 (N = 338), >100,000 (N = 122) copies/ml. Conclusions: Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART. [ABSTRACT FROM AUTHOR]