The misuse of prescription drugs in the U.S. is an alarming public health crisis. Prior research at the U.S.-Mexico border has found high rates of prescription drug misuse, but with rates varying significantly across border communities. We aimed to examine a model of permissive climate measures and stress exposures as potential mediators of community differences in prescription drug misuse at the U.S.-Mexico border. We analyzed data from the U.S.-Mexico Study of Alcohol and Related Conditions (UMSARC). Household, in-person interviews were conducted with Mexican-origin residents of the Texas border cities Laredo ( = 751) and Brownsville/McAllen ( = 814). Interviews assessed past-year misuse of any and pain-reliever prescription drugs. Drug availability, neighborhood safety, exposure to violence/crime, and social support were examined as potential mediators. Analyses were stratified by gender and employed regressions and mediation analysis with Mplus. The past-year prevalence of any prescription drug misuse in Laredo was 26.3% among women and 24.4% among men, and in Brownsville/McAllen was 12.4% among men, and 6.7% among women. Mediation analysis revealed site effects via some of the hypothesized risk factors for men, but not for women. Specifically, for men, site effects on any and pain reliever prescription drug misuse were partially mediated via high drug availability and low family support. Past-year prescription drug misuse was over 3 times the 2015 national prevalence among both men and women in Laredo and calls for immediate attention. Findings regarding the model suggest drug availability and social support may be relevant to understanding community differences in prescription drug misuse among men living at the border, and that additional factors should be investigated to understand misuse among women living at the border.