Background: An estimated 33% of adults in the United States have metabolic syndrome (MetS), which has been associated with an increased risk for various cancer types. Theories of synergism among components of MetS that increase cancer risk via chronic inflammation and oxidative stress have been proposed. We hypothesize that men and women with MetS may have compromised immunological response resulting in increased risk for persistent human papillomavirus (HPV) infection. The goal of this study is to determine the association of MetS with HPV types 6, 11, 16, and 18 and to explore variation of these associations by gender using data from a national survey. Methods: We conducted a retrospective cross-sectional study using data from the National Health and Nutrition Examination Survey. Results: Thirty-two percent of the population sampled met the criteria for MetS (16% men and 33% women). Nineteen percent tested positive for HPV (6, 11, 16, and 18). Prevalence of HPV infection was estimated at 13% for men and 30% for females. MetS was found to be significantly associated with increased risk of HPV6, 11, 16, or 18 in the entire cohort [RR = 1.24; 95% confidence interval (CI), 1.03–1.48] and in females (RR = 1.26; 95% CI, 1.02–1.56). Although the adjusted risk of HPV+ve status was found to be 21% higher in men with MetS compared with those without, this difference did not attain statistical significance. Conclusions: We observed a significant association between metabolic syndrome and HPV sero-positivity among the overall population and among females. Although not significant, a similar effect was noted in men. Further prospective studies are needed to better understand this relationship. Impact: To the best of our knowledge, this is the first study evaluating the impact of metabolic syndrome on HPV positivity in both males and females. Cancer Epidemiol Biomarkers Prev; 26(8); 1–7. ©2017 AACR.