Given the potential respiratory health risks, the association of COVID infection and the use of combustible cigarettes, electronic nicotine delivery systems (ENDS), and concurrent dual use is a priority for public health. Many published reports have not accounted for known covarying factors. This study sought to calculate adjusted odds ratios for self-reported COVID infection and disease severity as a function of smoking and ENDS use, while accounting for factors known to influence COVID infection and disease severity (i.e., age, sex, race and ethnicity, socioeconomic status and educational attainment, rural or urban environment, self-reported diabetes, COPD, coronary heart disease, and obesity status). Data from the 2021 U.S. National Health Interview Survey, a cross-sectional questionnaire design, were used to calculate both unadjusted and adjusted odds ratios for self-reported COVID infection and severity of symptoms. Results indicate that combustible cigarette use is associated with a lower likelihood of self-reported COVID infection relative to non-use of tobacco products (AOR = .64; 95% CI [.55, .74]), whereas ENDS use is associated with a higher likelihood of self-reported COVID infection (AOR = 1.30; 95% CI [1.04, 1.63]). There was no significant difference in COVID infection among dual users (ENDS and combustible use) when compared with non-users. Adjusting for covarying factors did not substantially change the results. There were no significant differences in COVID disease severity between those of varying smoking status. Future research should examine the relationship between smoking status and COVID infection and disease severity utilizing longitudinal study designs and non-self-report measures of smoking status (e.g., the biomarker cotinine), COVID infection (e.g., positive tests), and disease severity (e.g., hospitalizations, ventilator assistance, mortality, and ongoing symptoms of long COVID).