Smokers have higher levels of C-Reactive Protein (CRP) compared to never smokers. The role of smoking cessation on CRP is still under debate. Using data from two screening studies conducted in Italy in 2000-2010 on 3050 heavy smokers (including 777 ex-smokers), we estimated multivariate odds ratios (OR) for high CRP (i.e. ≥2 mg/L) according to smoking status. Moreover, in a longitudinal analysis based on 975 current smokers, with a second measurement of CRP after an average study period of 3.4 years, we estimated the changes in CRP according to smoking cessation. Prevalence of high CRP at baseline was 35.8% among ex-smokers and 41.1% among current smokers (significant OR for ex- vs. current smokers: 0.79). After four years since smoking cessation, CRP levels significantly decreased with increasing years of cessation (significant OR for ex-smokers since more than 8 years: 0.55). In the longitudinal analysis, no significant reduction in CRP was found for time since smoking cessation (ORs: 1.21, 1.04, and 0.91 for ex-smokers since 1 year, 2-3 years, and ≥4 years, respectively). In the largest prospective study available so far, we found that smoking cessation has a favourable effect on CRP, but this benefit is not evident in the short-term.