Objective: To investigate the effect of antioxidant supplementation on viral load and the antioxidant/reactive oxygen species system in people with HIV. Design: Single centre, prospective, dose comparison study. Setting: Outpatient clinic specializing in HIV care. Subjects: Sixty-six participants were sequentially recruited by advertisement, and 48 subjects completed the study. Interventions: A recommended dose antioxidant regimen (5450 IU vitamin A as beta -carotene, 250 mg vitamin C, 100 IU vitamin E, 100 mug selenium, 50 mg coenzyme Q10) or a high-dose antioxidant regimen (21 800 IU vitamin A as beta -carotene, 1000 mg vitamin C, 400 IU vitamin E, 200 mug selenium, 200 mg coenzyme Q10) for a 12 week period. Results: Using repeated measures analysis of variance, the changes over treatment time were significant for selenium, glutathione, glutathione peroxidase and lipid peroxides (P<0.03). Changes in allantoin, uric acid and viral load were not significant (P>0.05). The main effects for group and the interaction effects were not significant for any of the parameters measured (P greater than or equal to 0.05). Conclusion: Antioxidant supplementation significantly improved some measures of oxidative defence. There was no benefit in using a high-dose supplement in this study.