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BackgroundPolyfluoroalkyl chemicals (PFCs) are used commonly in commercial applications and are detected in humans and the environment worldwide. Concern has been raised that they may disrupt lipid and weight regulation.ObjectivesWe investigated the relationship between PFC serum concentrations and lipid and weight outcomes in a large publicly available data set.MethodsWe analyzed data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) for participants 12–80 years of age. Using linear regression to control for covariates, we studied the association between serum concentrations of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) and measures of cholesterol, body size, and insulin resistance.ResultsWe observed a positive association between concentrations of PFOS, PFOA, and PFNA and total and non-high-density cholesterol. We found the opposite for PFHxS. Those in the highest quartile of PFOS exposure had total cholesterol levels 13.4 mg/dL [95% confidence interval (CI), 3.8–23.0] higher than those in the lowest quartile. For PFOA, PFNA, and PFHxS, effect estimates were 9.8 (95% CI, −0.2 to 19.7), 13.9 (95% CI, 1.9–25.9), and −7.0 (95% CI, −13.2 to −0.8), respectively. A similar pattern emerged when exposures were modeled continuously. We saw little evidence of a consistent association with body size or insulin resistance.ConclusionsThis exploratory cross-sectional study is consistent with other epidemiologic studies in finding a positive association between PFOS and PFOA and cholesterol, despite much lower exposures in NHANES. Results for PFNA and PFHxS are novel, emphasizing the need to study PFCs other than PFOS and PFOA.