10606 Background: Organizational commitment and consistent leadership are crucial to facilitate implementation of workplace wellness programs. We aimed to investigate whether interactive assistance for SME managers to implement tobacco control programs (compared with usual practice) would increase 6-month abstinence rates in tobacco-smoking employees. Methods: This hybrid type II cluster randomized effectiveness implementation trial was done in Japan. SMEs in the intervention group received interactive assistance to employers and health managers for 6 months by supporting employees through campaigns, tailored ongoing facilitation, and ensuring executive engagement and support, aiming to promote utilization of reimbursed smoking cessation treatments and implement smoke-free workplaces. SMEs in the control group received feedback on the results of the baseline survey and information on smoking cessation measures. Stratified randomization was used to allocate SMEs to either group. The primary outcome was salivary cotinine-validated 7-day point-prevalence abstinence rate at 6 months, and the key secondary outcome was the adoption score of the two recommended measures (promote smoking cessation standard treatment visits, and smoke-free policy) at each SME at 6 months (range: 0–2). Other secondary outcomes included implementation and process outcomes (e.g., proportion of smoking cessation treatment use). Results: Between July 1, 2021, and May 16, 2022, 38 SMEs enrolled. Twenty SMEs were randomly assigned to the intervention group and 18 SMEs to the control group. Among 2,929 employees enrolled, 2,556 responded the baseline survey (response rate: 87.3%; men 65.0%; mean age 44.8 years) and 713 of them (27.9%) indicated being a current smoker in the baseline. Then 176 (6.9%) were omitted because of missing primary outcome data (mainly owing to not responding, turnover, resignation, or retirement); therefore, 537 participants (21.0%) were included in the intention-to-treat based analyses of the primary outcome. At 6 months, the validated 7-day point-prevalence abstinence rate in the intervention group was significantly higher than that in the control group (11.2% vs 4.6%; difference = 6.6%, 95% confidence interval: 2.2%–11.1%, p=0.004). Regarding the analysis for key secondary outcomes, all randomized SMEs were included. At 6 months, adoption score of the two recommended measures was also significantly higher than that in the control group (1.5 vs 1.1; difference = 0.4, 95% confidence interval: 0.01–0.86, p=0.047). Conclusions: Interactive support for SME managers to implement tobacco control measures (compared with usual practice) can accelerate the implementation of evidence-based smoking cessation measures and significantly increase 6-month abstinence rates. Clinical trial information: UMIN000044526.