Preclinical and clinical literature suggest that sex hormones impact tobacco use behaviors in women. The goal of this double-blind crossover laboratory study was to examine the effect of oral exogenous progesterone (200 mg twice per day) versus placebo on nicotine response using measures of motor speed and cognitive function in women following overnight smoking abstinence. We hypothesized that increased progesterone would blunt the nicotine response whereby producing less change in motor speed and cognition in response to nicotine exposure. Female smokers, age 18-35, were randomized to participate in two 9-day crossover testing weeks. Participants completed a lab session following overnight abstinence where they were administered nicotine nasal spray and asked to complete measures of immediate memory (IMT), delayed memory (DMT), word recall (WR), and finger tapping speed (FT). After the first 9-day testing week, participants resumed smoking and returned the following month to complete the identical lab session in the crossover condition. Forty-seven women were included in this analysis (n = 47). We found no differences in the magnitude of response for IMT, DMT, and WR between conditions. For FT, women had a blunted response to nicotine during the placebo condition. When examining the association between hormone levels and relative performance, we found increases in DMT, WR, and FT but decreases in IMT during the progesterone condition. We observed differences between progesterone versus placebo in relative change in some measures of nicotine response following overnight abstinence. Future studies are needed to further characterize this response. (PsycInfo Database Record (c) 2020 APA, all rights reserved).