Iron and lipids combine to create oxidative stress, and oxidative stress has a role in the development of cancer. The objective was to determine the risk of cancer among persons who had both elevated iron and lipids. The authors conducted an analysis of the cohort available in the Framingham Offspring Study. Adults aged 30 or more years at baseline had serum iron and high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, and very low density lipoprotein cholesterol (VLDL-C) assessed in 1979-1982 and were followed for development of cancer until 1996-1997 (n = 3,278). Cox regression models were computed while controlling for age, gender, smoking status, and body mass index. In adjusted models, both elevated iron (hazard ratio (HR) = 1.66, 95% confidence interval (CI): 1.11, 2.46; 29 cases) and VLDL-C (HR = 1.54, 95% CI: 1.04, 2.28; 93 cases) had significant independent risks for development of cancer. When elevated iron was combined with elevated VLDL-C, the adjusted relative risk of cancer increased (HR = 2.68, 95% CI: 1.49, 4.83; 18 cases). Elevated iron and low HDL-C also had a significant adjusted relative risk of cancer (HR = 2.82, 95% CI: 1.50, 5.28; 14 cases). The results suggest that elevated serum iron levels coupled with either high VLDL-C or low HDL-C appear to interact to increase cancer risk in this cohort.