Hookah smoking has grown to become a global tobacco epidemic. While cigarette smoking is a well-established cardiovascular disease (CVD) risk factor, the CVD risks of hookah smoking are unknown, particularly among regular U.S. adult hookah users who are predominantly non-daily users. Herein, we examined the association between hookah smoking and biomarkers of CVD risk among regular exclusive hookah smokers (n = 75), compared to regular exclusive cigarette smokers (n = 1773), dual hookah and cigarette smokers (n = 43) and never tobacco users (n = 757), using data from a nationally representative sample of adults from the Population Assessment of Tobacco and Health Study (2013-2014). Whereas 84% of cigarette smokers reported daily use, only 8% of hookah smokers reported daily use, with more than a third reporting monthly use. Adjusting for age and sex and as compared to exclusive cigarette smokers, exclusive hookah smokers had significantly lower geometric mean concentrations in serum sICAM-1 and urinary F2-isoprostane (p < 0.05). Although not statistically significant, a signal of increased oxidative stress was observed among hookah smokers as compared to never tobacco users (urinary F2-isoprostane). CVD-related harm biomarkers appear to be lower among hookah smokers than cigarette smokers. These findings represent patterns of hookah smoking predominantly shared among adult U.S. users who report non-daily occasional use and do not reflect solitary, daily use as is common in the Middle East. Future studies with longer exposure and longitudinal hookah use are warranted to explore the association between hookah smoking and CVD risk.