Abstract Background Adults with chronic disease are often unable to meet medication and food needs, but no study has examined the relationship between cost-related medication underuse and food insecurity in a nationally representative sample. We examined which groups most commonly face unmet food and medication needs. Methods Cross-sectional analysis of data from chronically ill participants (self-report of arthritis, diabetes mellitus, cancer, asthma, chronic obstructive pulmonary disease, stroke, hypertension, coronary heart disease, or presence of a “psychiatric problem”) aged ≥20 years, in the 2011 National Health Interview Survey. We fit logistic regression models to identify factors associated with food insecurity, cost-related medication underuse, or both. Results There were 9696 adult National Health Interview Survey (NHIS) participants who reported chronic illness; 23.4% reported cost-related medication underuse; 18.8% reported food insecurity; and 11% reported both. Adults who reported food insecurity were significantly more likely to report cost-related medication underuse (adjusted odds ratio aOR 4.03). Participants with both cost-related medication underuse and food insecurity were more likely to be Hispanic (aOR 1.58), non-Hispanic black (aOR 1.58), and have more chronic conditions (aOR per additional chronic condition 1.56) than patients reporting neither. They also were less likely to have public, non-Medicare insurance (aOR 0.70) and report participation in the Special Supplemental Nutrition Assistance Program for Woman, Infants, and Children (aOR 0.39). Conclusions Approximately 1 in 3 chronically ill NHIS participants are unable to afford food, medications, or both. WIC and public health insurance participation are associated with less food insecurity and cost-related medication underuse.