Background: HIV-infected individuals have increased risk of developing obstructive lung disease (OLD). Studies from developed countries report high viral load, low CD4 counts, and anti-retroviral therapy (ART) to be associated with OLD; but these findings may not be generalizable to populations in resource-limited settings. Methods: We conducted a prospective cohort study of lung function in 730 HIV-infected black South African adults. Pre-bronchodilator spirometry was performed at enrollment and repeated annually for three years. Logistic regression models were used to identify factors associated with OLD, defined as FEV1/FVC<0.70, at enrollment. Excess annual declines in FEV1 and FVC were modelled as the product-term of follow-up time and exposures using random effects regression. Results: Median (IQR) age at enrollment was 36 (32-41) years, 85% were female and 30% ever-smoked with a median (IQR) exposure of 3 (1-6) pack-years. Median (IQR) CD4 count and viral load at enrollment were 372 (261-518) cells/mm3 and 2655 (91-13,548) copies/mL respectively. Overall, 25% were receiving ART at enrollment, 16% of whom reported at least 6 months of ART receipt. OLD was found in 35 (5%) at enrollment. Increasing age (aOR=2.08 per 10-years [95%CI 1.22-3.57], p=0.007), current smoking (aOR=3.55 [95%CI 1.20-10.53], p=0.02), and CRP (aOR=1.01 per unit-increase [95%CI 1.00-1.03], p=0.04) were significantly associated with OLD at enrollment; while increasing CD4 count (aOR=1.02 per-100 cells/mm3 [95%CI 0.85-1.22], p=0.82), viral load (aOR=0.67 per log-increase [95%CI 0.43-1.10], p=0.12) and receipt of ART (aOR=0.57 [95%CI 0.18-1.75], p=0.32) were not. The median (IQR) follow-up time was 18 (12-24) months. Participants with a history of tuberculosis (TB) had a 35 mL (95%CI 2-68, p=0.03) and 57 mL (95%CI 19-96, p=0.003) per year excess loss of FEV1 and FVC respectively. Conclusion: Prevalent OLD was associated with older age, current smoking and higher CRP levels, but not CD4 counts and ART, in HIV-infected South African adults. Better understanding of the long-term effects of TB, smoking and inflammation on lung function in HIV-infected populations is urgently needed.