<p>This cross-sectional study included 18,797 participants from 6 longitudinal cohorts (CARDIA, FHS Gen III, HCHS/SOL, MESA, MiHeart, and REGARDS), and 5,806 of them had high-sensitivity C-reactive protein (hs-CRP) measurements. We found that exclusive electronic cigarette (EC) use was associated with significantly lower hs-CRP levels compared to exclusive combustible cigarette use, suggesting a potentially lower inflammatory burden. hs-CRP levels in dual users and former smokers currently using EC were comparable to those observed in exclusive cigarette smokers. Exclusive EC users showed no significant difference in hs-CRP levels compared to never cigarette smokers. These findings have important implications for tobacco regulation, public health, and clinical practice, highlighting the need for continued monitoring of potential EC-related health impacts.</p>