Background and Rational:
Electronic cigarettes (EC), mainly with nicotine content, are widely used worldwide. Although the number of publications about its use is increasing exponentially, evidence-based, unbiased, conclusive, head-to-head comparisons about its efficacy and safety as an aid for smoking cessation are lacking.

Methods and analysis:
Design: Randomized, placebo and reference treatment-controlled, multicenter, double-blind, double-dummy, parallel-group trial. Participants: Smokers smoking at least ten cigarettes/day in the past year and motivated to quit, aged 18–70 years.

Interventions:
1. EC without nicotine (ECwoN) plus placebo tablets of varenicline administered by oral route: placebo condition
2. EC with nicotine (ECwN) plus placebo tablets of varenicline: ECwN condition Voltage regulated electronic cigarettes will be used with liquid containing 12 mg/mL of nicotine for ad libitum use—flavour, blond tobacco.
3. ECwoN plus 0.5 mg varenicline tablets (Ref.): varenicline condition. Varenicline administered according to the marketing authorisation. Treatment duration: 1 week + 3 months. Follow-up at six months.

Outcomes:
Primary outcome: continuous smoking abstinence rate (CAR) (abstinence from conventional/combustible cigarettes) during the last four weeks (weeks 9 to 12) of the treatment period defined as self-report of no smoking during the previous two weeks and expired air CO ≤8 ppm at Visit 4 at Week 10 after the target quit date (TQD), i.e. 11 weeks after treatment initiation AND at Visit 5, Week 12 after TQD, i.e. 13 weeks after treatment initiation. Secondary outcomes: Safety profile; continuous abstinence rate from target quit date, point prevalence abstinence rate; CAR confirmed by urinary anabasine concentration; changes in cigarettes/day consumption, craving for tobacco and withdrawal symptoms with respect to baseline. Between 17 October 2018 and 10 March 2020, 328 smokers were randomised.