Abstract: The purpose of the present study was to explore the differences in illicit drug use and opioid misuse according to the sexual orientation of spouses in the military and spouses not in the military. Data were retrieved from the 2015-2019 waves of the National Survey of Drug Use and Health (military n = 905; civilian n = 1,865). Differences in drug use and opioid misuse by sexual orientation and military status were tested in stratified Poisson regression models, adjusting for sociodemographic variables, psychological distress, and health conditions. Any drug use in the past year was higher among spouses of active-duty service members (4.42%) than among spouses of civilians (1.55%, chi(2) = 20.59, p < .001). Any opioid misuse was higher among spouses of active-duty service members (7.29%) than among spouses of civilians (4.29%, chi(2) = 11.01, p = .001). In adjusted models, sexual minority status was a risk factor for drug use, but not opioid misuse, among military spouses; however, sexual minority status was a risk factor for both drug use and opioid misuse among civilian spouses. We showed that illicit drug use among spouses of active-duty service members may be higher than spouses of civilians, especially for sexual minorities; however, sexual minority status may only be a risk factor for civilian couples.