Electronic cigarettes (e-Cigarette) are battery-operated devices designed to vaporise nicotine that may aid smokers to quit or reduce their cigarette consumption. Research on e-Cigarettes is urgently needed to ensure that the decisions of regulators, healthcare providers and consumers are evidence based. Here we assessed long-term effectiveness and tolerability of e-Cigarette used in a 'naturalistic' setting. This prospective observational study evaluated smoking reduction/abstinence in smokers not intending to quit using an e-Cigarette ('Categoria'; Arbi Group, Italy). After an intervention phase of 6 months, during which e-Cigarette use was provided on a regular basis, cigarettes per day (cig/day) and exhaled carbon monoxide (eCO) levels were followed up in an observation phase at 18 and 24 months. Efficacy measures included: (a) ≥50% reduction in the number of cig/day from baseline, defined as self-reported reduction in the number of cig/day (≥50%) compared to baseline; (b) ≥80% reduction in the number of cig/day from baseline, defined as self-reported reduction in the number of cig/day (≥80%) compared to baseline; (c) abstinence from smoking, defined as complete self-reported abstinence from tobacco smoking (together with an eCO concentration of ≤10 ppm). Smoking reduction and abstinence rates were computed, and adverse events reviewed. Of the 40 subjects, 17 were lost to follow-up at 24 months. A >50% reduction in the number of cig/day at 24 months was shown in 11/40 (27.5%) participants with a median of 24 cig/day use at baseline decreasing significantly to 4 cig/day (p = 0.003). Smoking abstinence was reported in 5/40 (12.5%) participants while combined >50% reduction and smoking abstinence was observed in 16/40 (40%) participants at 24 months. Five subjects stopped e-Cigarette use (and stayed quit), three relapsed back to tobacco smoking and four upgraded to more performing products by 24 months. Only some mouth irritation, throat irritation, and dry cough were reported. Withdrawal symptoms were uncommon. Long-term e-Cigarette use can substantially decrease cigarette consumption in smokers not willing to quit and is well tolerated. ( http://ClinicalTrials.govnumberNCT01195597 ).