Background: Although the detrimental effects of conventional combustible cigarettes on oral health and dental esthetics are well known, there is limited information about the long-term impact of combustion-free nicotine alternatives (C-F NA) such as e-cigarettes or heated tobacco products. Objective: This multicenter, prospective, 3-parallel-arm randomized controlled trial will investigate whether switching from combustible cigarettes to C-F NA will lead to measurable improvements in oral health parameters and dental esthetics over 18 months in adult smokers with limited gum disease. Methods: Regular smokers not intending to quit and without clinical signs of periodontitis will be randomly assigned (1:4 ratio) to either standard of care with brief cessation advice (control group; arm A) or C-F NA use (intervention group; arm B). The study will also include a reference group of never smokers (reference group; arm C). The primary end point is the change in the Modified Gingival Index (MGI) score from baseline between the control arm (arm A) and the intervention arm (arm B) at the 18-month follow-up. In addition, the study will analyze the within- and between-group (arms A, B, and C) changes in MGI assessment, plaque imaging, dental shade quantitation, tooth stain scores, and oral health–related quality of life questionnaires measured at each study time point. All participants will attend a total of 7 clinic visits: screening, enrollment, and randomization (visit 0); baseline visit—day 14 (visit 1); day 90 (visit 2); day 180 (visit 3); day 360 (visit 4); and day 540 (visit 5). This multicenter study will be conducted in 4 dental clinics in 4 countries. The statistical analysis will involve descriptive statistics for continuous and categorical data. Primary end points will undergo tests for normality and, based on distribution, either a 2-sided t test or Mann-Whitney U test. Linear mixed model with random factors center and study arms by center will also be applied. Secondary end points, including MGI assessment and quality of life, will be subjected to similar tests and comparisons. Only if one value of the parameter MGI is missing after day 1, the last available observation will be carried forward. The analysis will be performed on the substituted data. Secondary parameters will not have missing value replacement. Results: Participant recruitment began in October 2021, and enrollment was completed in June 2023. Results will be reported in 2025. Conclusions: This will be the first study to provide key insights into oral health benefits or risks associated with using C-F NA in smokers who are seeking alternatives to cigarette smoking.