Background: The harm from smoking results mainly from long-term exposure to harmful and potentially harmful constituents (HPHC) in cigarette smoke generated by the combustion of tobacco. Smoking cessation (SC) is the most effective way to reduce the harm and risk of smoking-related diseases. In most SC studies, the main focus is on the rate of successful quitting for the SC approach/treatment tested; only limited information on multiple short- to long-term functional/ biological changes following SC is available in the literature. The overall study aim was to assess, over a one-year period of continuous smoking abstinence, the reversibility of the harm caused by smoking by assessing changes in clinical risk endpoints (CRE) linked to the pathophysiological pathways underlying the development of smoking-related diseases. Methods: This was a multicenter (42 sites), multiregional (U.S., Europe, Japan) SC study in healthy adult smokers planning to quit smoking within the next 30 days who were asked to continuously abstain from smoking during a one-year period in an ambulatory setting. Results: The study enrolled 1184 subjects (50.1% male), with 30% having successfully quit smoking for one year. The study showed favorable changes in several CREs linked to cardiovascular diseases (CVD), as indicated by a decrease from baseline in WBC, 11-DTX-B2, 8-epi-PGF2α, and sICAM-1; a slight decrease in homocysteine and fibrinogen; and a slight increase in HDL-C. For some other CREs associated with CVD (Apo A1 and B, LDL-C, hs-CRP, platelets, Albumin, and HbA1c) and respiratory functions, no major changes from baseline were observed after one year of smoking abstinence. Levels of all the biomarkers of exposure to HPHCs, including COHb and Total NNAL, were substantially reduced, ranging from –54.5% to –97.9%. Conclusions: These results indicate that continuous abstinence from smoking for one year leads to a substantial reduction in exposure to HPHCs and favorable changes in multiple mechanistic pathways and biological functions, such as lipid metabolism, inflammation, or oxidative stress, that are likely to contribute to the reduction of risk of developing smoking-related diseases.