This study aims to compare serum cotinine levels in e-cigarette and combustible cigarette smokers, in an attempt to quantify the potential chronic nicotine addiction risk that e-cigarettes pose. We analyzed 428 participants in 2015–2016 NHANES: 379 (87.03%) smoked combustible cigarettes alone and 49 (12.97%) smoked e-cigarettes. Serum cotinine levels were measured by isotope-dilution high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometric method with a detection limit of 0.015 ng/ml. Electronic cigarette smokers were younger than combustible cigarette smokers (mean age 36.79 versus 42.69 years, P = 0.03), more likely to be male (64.93% versus 48.32%, P = 0.09) and significantly less likely to live with other smokers (50.17% versus 90.07%, P < 0.01). Serum cotinine levels increased linearly with self-reported days of smoking in both electronic cigarette and combustible cigarette smokers, after accounting for living with a smoker. The analysis of the subgroup who reported daily use show non-statistically significantly higher serum cotinine levels in electronic cigarette smokers versus combustible cigarette smokers (β _adj = 52.50, P = 0.10). This analysis of recent US data demonstrates that electronic cigarettes expose users to nicotine levels proportionate to, and potentially higher than combustible cigarettes, and thus pose a serious risk of chronic nicotine addiction. This could be particularly relevant in otherwise tobacco naive individuals; future risk of tobacco-related dependence, addiction and relapse, as well as of tobacco-related cancers in these subjects needs to be investigated.