Grandparents in rural Appalachia with primary caregiving responsibilities for their grandchildren often struggle with high levels of stress, inadequate resources, and poor physical and mental health. However, implications for children of being raised by grandparents rarely have been examined, particularly in terms of stress biomarkers. The present study investigated salivary C-reactive protein, interleukin-6, and tumor necrosis factor alpha in a small sample of children ( = 20) aged 5 to 18 years being reared by grandparents in two rural counties in Kentucky, a region well known for its resource scarcity. Saliva samples were collected from children 30 min after waking at two time points spaced one year apart. Grandparents and children completed a series of questionnaires via interview. Children's internalizing symptoms were related to greater markers of inflammation over time. Grandparent stress and poor mental health were also related to greater inflammation, while grandparent positive parenting and religiosity were associated with lower inflammation.