PurposeTo examine the effectiveness, cost-outcome, equity, scalability, and mechanisms of the Reach Out, Stay strong, Essentials for mothers of newborns (ROSE) postpartum depression prevention (PPD) program as universal versus selective or indicated prevention. BackgroundThe United States Preventive Services Task Force (USPSTF) currently recommends PPD prevention for pregnant people at risk of PPD (i.e., selective/indicated prevention). However, universal prevention may be more scalable, equitable, and cost-beneficial. DesignEffectiveness of ROSE for preventing PPD among people at risk is known. To assess ROSE as universal prevention, we need to determine the effectiveness of ROSE among all pregnant people, including those screening negative for PPD risk. We will enroll 2320 pregnant people, assess them with commonly available PPD risk prediction tools, randomize everyone to ROSE or enhanced care as usual, and assess ROSE as universal, selective, and indicated prevention in terms of: (1) effectiveness (PPD prevention and functioning), (2) cost-benefit, (3) equity (PPD cases prevented by universal prevention that would not be prevented under selective/indicated for minority vs. non-Hispanic white people), (4) quantitative and qualitative measures of scalability (from 98 agencies previously implementing ROSE), (5) ROSE mechanisms across risk levels. We will integrate results to outline pros and cons of the three prevention approaches (i.e., universal, selective, indicated). ConclusionThis will be the first trial to assess universal vs. selective/indicated PPD prevention. Trial design illustrates a novel, efficient way to make these comparisons. This trial, the largest PPD prevention trial to date, will examine scalability, an understudied area of implementation science.