Project Summary/Abstract Postpartum smoking relapse rates have remained stagnant for over a decade with more than 50% of those who are able to achieve smoking abstinence during pregnancy relapsing within the first few months after childbirth. Maternal cigarette smoking results in significant increases in a variety of negative health consequences for both mother and child. Second-hand smoke exposure to newborns and infants increases their risk of both acute and chronic illness. Therefore, research to identify safe and novel postpartum smoking relapse prevention intervention is warranted. Our preliminary data indicates that the delivery of exogenous progesterone (Prog) in the early postpartum period reduces several smoking relapse related risk factors (e.g., craving) and was also associated with a higher prevalence of smoking abstinence at 12-weeks postpartum. These observations concur with a wealth of prior literature that demonstrates the protective effects of progesterone on a variety of addictive behaviors. In our other preliminary work looking at non-pregnant premenopausal women, depot medroxyprogesterone acetate or DMPA, which blocks ovulation for 12-weeks which subsequently decreases estradiol levels, was associated with longer previous quit attempts and reduced smoking motives. These observations have shaped our central hypothesis which is that the combination of Prog + DMPA; i.e., increased progesterone and decreased estradiol will prevent postpartum smoking relapse. To examine this hypothesis, we will conduct a double-blind, placebo-controlled, randomized clinical trial that will be implemented by an experienced, transdisciplinary, and productive team of investigators from two sites to enhance the diversity of the study sample and generalizability of the results. We will enroll healthy pregnant women (n=320) who have recently quit smoking and intend to stay abstinent postpartum. Using a 2×2 factorial design, participants will be randomized into one of four assignments: (1) Prog + DMPA, (2) Prog + placebo, (3) placebo + DMPA, and (4) placebo + placebo. Participants will be followed for days to smoking relapse (primary outcome), smoking relapse-related risk factors (e.g., craving), and infant health outcomes from gestational week 36 through 9 months postpartum. This study proposes a safe and innovative intervention to examine the impact of manipulating postpartum physiological to influence the behavior of a new mother which will lead to improved health outcomes for her and her infant. The implications of this novel study will directly advance the current state of the science by expanding on the role of Prog and DMPA in addressing smoking-related behaviors within this highly vulnerable population. Further, should our central hypothesis be supported, the clinical translatability of this intervention is high and may be immediately pursued.