Abstract Introduction A smoking-cessation program was implemented as a randomized non-inferiority trial in primary care practices in Croatia and Slovenia to investigate whether a standard 4-week treatment with cytisine was at least as effective and feasible as a standard 12-week treatment with varenicline in helping smokers quit. Aims and Methods Out of 982 surveyed smokers, 377 were recruited to the non-inferiority trial: 186 were randomly assigned to cytisine and 191 to varenicline treatment. The primary cessation outcome was 7-day abstinence after 24 weeks, while the primary feasibility outcome was defined by adherence to the treatment plan. We also compared the rates of adverse events between the two treatment groups. Results The cessation rate after 24 weeks was 32.46% (62/191) in the varenicline group and 23.12% (43/186) in the cytisine group (odds ratio OR: 0.63, 95% credible interval CI: 0.39 to 0.98). Of 191 participants assigned to varenicline treatment 59.16% (113) were adherent, while 70.43% (131 of 186) were adherent in the cytisine group (OR: 1.65, 95% CI: 1.07 to 2.56). Participants assigned to cytisine experienced fewer total (incidence rate ratio IRR: 0.59, 95% CI: 0.43 to 0.81) and fewer severe or more extreme adverse events (IRR: 0.72, 95% CI: 0.35 to 1.47). Conclusions This randomized non-inferiority trial (n = 377) found the standard 4-week cytisine treatment to be less effective than the standard 12-week varenicline treatment for smoking cessation. However, adherence to the treatment plan, ie, feasibility, was higher, and the rate of adverse events was lower among participants assigned to cytisine treatment. Implications The present study found the standard 12 weeks of varenicline treatment to be more effective than the standard 4 weeks of cytisine treatment for smoking cessation in a primary care setting in Croatia and Slovenia. Participants assigned to cytisine, however, had a higher adherence to the treatment plan and a lower rate of adverse events. Estimates from the present study may be especially suitable for generalizations to high-smoking prevalence populations in Europe. Given the much lower cost of cytisine treatment, its lower rate of adverse events, and higher feasibility (but its likely lower effectiveness with the standard dosage regimen), future analyses should assess the cost-effectiveness of the two treatments for health policy considerations.