We examined the primary preventive effect of vitamin E (alpha-tocopherol) and beta-carotene supplementation on intermittent claudication. The subjects--participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study--were male smokers aged 50 to 69 years who were randomly assigned to receive 50 mg of alpha-tocopherol daily, 20 mg of beta-carotene daily, both, or placebo. At baseline, there were 26 289 men with no history or symptoms of intermittent claudication. The Rose questionnaire on intermittent claudication was administered annually to discover incident cases. We observed 2704 cases of first occurrence of typical intermittent claudication during a median follow-up time of 4.0 years. Compared with placebo, the adjusted relative risk for typical intermittent claudication among those who received alpha-tocopherol only was 1.11 (95% confidence interval, 1.00-1.24); among those who received alpha-tocopherol and beta-carotene, 1.02 (0.91-1.13); and among those who received beta-carotene only, 1.02 (0.92-1.14). When we compared the alpha-tocopherol-supplemented subjects with those who received no alpha-tocopherol, the adjusted relative risk for typical intermittent claudication was 1.05 (0.98-1.14), and for beta-carotene-supplemented subjects compared with those who did not receive beta-carotene, the relative risk was 0.96 (0.89-1.04). In conclusion, no primary preventive effect on intermittent claudication was observed among middle-aged male smokers who were supplemented with alpha-tocopherol, beta-carotene, or both.