Pregnancy presents an opportunity to engage expectant fathers in smoking cessation, but evidence from randomized clinical trials is scarce. To evaluate the effectiveness of a proactive, combined intervention for smoking cessation in expectant fathers. This pragmatic randomized clinical trial in prenatal clinics in 7 public hospitals in Hong Kong proactively recruited and enrolled 1053 participants from October 10, 2018, to February 8, 2020. Included male adults were 18 years or older, smoked cigarettes daily in the past 3 months, had partners who were pregnant and nonsmoking in the past 30 days, and had a landline or mobile telephone number for follow-up. These participants were randomized to either the intervention group or the control group. The primary analyses used an intention-to-treat approach. The intervention group received brief cessation advice, a 1-week free sample of nicotine replacement therapy (NRT), and active referral to a community-based smoking cessation service. The control group received only brief cessation advice with a leaflet on the hazards of perinatal exposure to tobacco smoke and the toll-free quitline telephone number. The primary outcome was biochemically validated tobacco abstinence at 6 months after intervention initiation defined by an exhaled carbon monoxide level of 3 parts per million or lower. The secondary outcomes included self-reported 24-week continuous abstinence at 6 months after intervention initiation as well as 7-day point prevalence abstinence, use of any NRT, and use of a smoking cessation service at 3 and 6 months after intervention initiation. All 1053 randomized participants were male adults with a mean (SD) age of 33.8 (6.9) years. The retention rate at 6-month follow-up was 80.7%. The primary outcome of biochemically validated tobacco abstinence at 6 months after intervention initiation was significantly higher in the intervention group than in the control group (6.8% [36 of 527 participants] vs 3.6% [19 of 526]; odds ratio [OR], 1.96; 95% CI, 1.11-3.46; P = .02). The main secondary outcomes of self-reported 24-week continuous abstinence at 6 months (OR, 1.87; 95% CI, 1.08-3.23; P = .03) and 7-day point prevalence abstinence at 3 months (OR, 1.48; 95% CI, 1.05-2.09; P = .03) and 6 months (OR, 1.74; 95% CI, 1.29-2.34; P < .001) were also significantly higher in the intervention group. The intervention group had a significantly higher increase in perceived family harmony (score range, 0-10, with a higher score indicating a higher level of harmony) from baseline to 6 months (B = 0.28; 95% CI, 0.063-0.50; P = .01). This trial found that combining brief advice with a 1-week sample of NRT and referral to smoking cessation programs nearly doubled the odds that expectant fathers who smoked would achieve validated abstinence compared with providing brief advice alone. The intervention was also effective in promoting family harmony. ClinicalTrials.gov Identifier: NCT03671707.