Prescription drug misuse in older adults is a growing public health problem. It is important to understand factors which predispose older adults to misuse prescription drugs, and social isolation may play an important role. In this study, we examined the association between social isolation proxy variables (living alone, being unmarried, and not attending religious services) and prescription opioid/benzodiazepine misuse in older adults.With pooled cross-sectional data from the National Survey on Drug Use and Health (2015-2017), we used multinomial multiple logistic regression models to analyze the association between each social isolation proxy variable and past-year prescription opioid/benzodiazepine misuse. We controlled for potentially confounding variables including sociodemographic, physical/mental health, and substance use variables.Being unmarried was associated with approximately three times increased odds of combined opioid and benzodiazepine misuse (OR 2.98, 95% CI 1.75, 5.08), a finding that persisted after adjusting for multiple potential confounders. Further analysis showed this finding persisted for divorced/separated and never married individuals, but not widowed. Not attending religious services was also associated with prescription opioid/benzodiazepine misuse, but only in unadjusted analyses. There was no association between living alone and opioid/benzodiazepine misuse.Increased odds of combined opioid and benzodiazepine prescription drug misuse was observed among unmarried older adults. Given the susceptibility of older adults to the harms of these medications, further exploration of the role of marital relationships and other forms of social connectedness in prescription drug misuse in this vulnerable population is indicated.