We have recently published efficacy and safety data of a study using an oral nicotine inhaler in smoking reduction. The current analysis was undertaken to assess the secondary objectives of the trial: the influence of long-term smoking reduction on health risk markers. Four hundred healthy volunteers, unable or unwilling to stop smoking immediately, were enrolled in a double-blind, randomized, placebo-controlled trial in smoking reduction; 310 were evaluable up to 2 years. Participants were randomized to active or placebo inhalers as needed for up to 18 months, with subjects encouraged to reduce their smoking as much as possible; counseling took place over a 2-year period. For the current prospective cohort study, the number of daily cigarettes, carbon monoxide (CO), cotinine, cardiovascular risk factors, pulmonary function tests, and quality of life were compared between successful reducers (n = 25) and unsuccessful reducers (control group, n = 285). Success was defined as a reduction of daily cigarettes of at least 50% from week 6 to 2 years, verified by a decrease in exhaled CO at all visits compared with baseline. At 2 years, successful reducers showed a significantly greater decrease in cotinine levels (60% vs. 1%, p < 0.001), cholesterol/high-density lipoprotein (HDL) ratios (−2.42 vs. −1.67, p = 0.025), hemoglobin concentrations (−5.67 vs. −1.34 g/l, p = 0.023), pulse rate (−3.7 vs. +1.0 bpm, p = 0.043), and significantly improved general health score (9.40 vs. 2.34, p = 0.049); whereas no difference was found in forced expiratory volume during 1 s (FEV1) and forced vital capacity (FVC) compared with controls. The benefits of long-term smoking reduction of at least 50% of daily cigarettes were not offset by compensatory smoking, and the marked decrease in markers of smoke exposure had a positive influence on several cardiovascular risk markers and quality of life assessments.