The authors conducted a nested case-control study from 1992 to 2003 among US women aged 45 years or older and free from cardiovascular disease and cancer to examine the prospective association among plasma lycopene, other carotenoids, and the risk of developing type 2 diabetes. During 10 years of follow-up, 470 cases of incident type 2 diabetes were selected and individually matched on age (+/- 1 year) and follow-up time to 470 nondiabetic controls. Baseline plasma levels of lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin were similar in cases and controls (all p > 0.05). A possible crude inverse association between plasma lycopene and risk of type 2 diabetes was attenuated upon multivariate adjustment. After control for plasma total cholesterol and known diabetes risk factors, the multivariate odds ratios of type 2 diabetes in the highest versus the lowest quartile of plasma carotenoids were 1.13 (95% confidence interval (CI): 0.60, 2.13) for lycopene, 1.27 (95% CI: 0.63, 2.57) for alpha-carotene, 1.10 (95% CI: 0.57, 2.13) for beta-carotene, 0.91 (95% CI: 0.46, 1.81) for beta-cryptoxanthin, and 1.35 (95% CI: 0.68, 2.69) for lutein/zeaxanthin. There was no prospective association between baseline plasma carotenoids and the risk of type 2 diabetes in middle-aged and older women.