OBJECTIVE The Self-Medication Hypothesis (SMH) theorizes that alcohol is used to alleviate negative states. We assessed whether an acute social stressor (Trier Social Stress Test, TSST), a priming dose of alcohol, and participant sex impacted 90-min ad libitum drinking. We expected exposure to stress to be associated with increased consumption, and this effect to be stronger following an alcohol priming dose; we also explored whether participant sex moderated these effects. METHODS Using a 2×2 experimental design, we randomized groups of two to three drinkers to stress (TSST vs. no TSST) and priming beverage (alcohol vs. placebo) conditions. All participants subsequently completed the 90-min ad libitum drinking period and were instructed not to exceed more than one alcoholic beverage per hour for optimal performance to model behavioral impaired control. We examined (a) number of drinks ordered, (b) violations of the drink limit, (c) change in breath alcohol concentration (BAC), and (d) peak BAC. RESULTS Analyses showed that exposure to stress was associated with heavier ad libitum drinking. This effect was qualified by a three-way interaction; women who received a stressor and no prime dose (placebo) reached higher BACs, whereas men who received a stressor and a prime reached higher BACs. CONCLUSIONS The hypothesized interaction between an alcohol priming dose and social stress was only evident among men, whereas women drank more under social stress in the absence of a priming dose. Findings suggest the importance of exploring sex differences in future studies of the SMH. (PsycInfo Database Record (c) 2022 APA, all rights reserved).