Objective-To evaluate longitudinal changes in 6 inflammatory markers that predict cardiovascular disease events among smokers making a quit attempt and to characterize their cross-sectional associations between smoking and smoking heaviness. Approach and Results-In a longitudinal cohort study of contemporary smokers (n=1652), we evaluated (1) independent associations of smoking heaviness markers (exhaled carbon monoxide, cigarettes/d, pack-years) with inflammatory markers (C-reactive protein, D-dimer, fibrinogen, urinary F-2 isoprostane: creatinine [F-2:Cr] ratio, white blood cell [WBC] count, myeloperoxidase) and (2) the effects of smoking cessation and continued smoking on these inflammatory markers after 1 year, among the 888 smokers who made an aided quit attempt as part of a randomized comparative effectiveness trial or standard care. There were strong, independent associations between smoking heaviness markers and the F-2:Cr ratio, WBC, and myeloperoxidase (all P-adj<0.001), but not high-sensitivity C-reactive protein, D-dimer, or fibrinogen. Participants were mean (SD) 49.6 years old (11.6), 54% women, 34% non-white, and smoked 16.8 cigarettes/d (8.5) for 27.3 pack-years (18.6). After 1 year, the 344 successful abstainers gained more weight (4.0 [6.0] versus 0.4 [5.7] pounds; P<0.001) and had larger increases in insulin resistance scores (P=0.02) than continuing smokers. Despite these increases, abstainers had significant decreases in F-2:Cr ratio (P<0.001) and WBC counts (P<0.001). Changes in other markers were not related to quitting. Conclusions-Smoking heaviness is associated with increased F-2:Cr ratio, myeloperoxidase, and WBC counts. Cessation improves the F-2:Cr ratio and WBC counts independent of weight change, suggesting reduced inflammation related to less oxidant stress.