Objective: We assessed whether general practitioner (GP) delivery of a vaginal self-sampling kit was non-inferior to home-mailed delivery on cervical cancer screening (CCS) participation. Methods: Two hundred and ten French GPs from Indre-et-Loire French department were randomized into two groups, and their unscreened women patients aged 30-65 were included in February-March 2015. In the GP delivery group (n = 105 GPs; 1,806 women), women were sent a reminder letter inviting them to collect a vaginal self-sampling kit at their regular GP's practice. In the home-mailed delivery group (n = 105 GPs; 1,806 women), women were sent a reminder letter with a vaginal self-sampling kit directly at home. The primary outcome was participation in complete CCS within 9 months. A cost-effectiveness analysis was also performed. Results: At 9 months, 14.9% (95% CI: 12.9-16.9) and 27.9% (95% CI: 25.7-30.0) of women in the GP and home-mailed delivery groups participated in complete CCS. The absolute between-group difference was -13.0 percentage points (95% CI: -15.9 to -10.0) in favor of the home-mailed delivery group, crossing the non-inferiority pre-defined non-inferiority margin of 5%. The home-mailed delivery strategy cost 50.81€ more per additional woman screened. Conclusions: The GP delivery was inferior to home-mailed delivery in increasing participation in CCS. Home-mailed delivery of a vaginal self-sampling kit is a cost-effective way to increase CCS in that the additional cost of this strategy seems acceptable. This study is registered at www.Clinicaltrials.gov NCT02255084.