OBJECTIVES: Rural-urban disparities in the experiences of caregivers of older adults with advanced cancer may exist. This study examined factors associated with caregiver mastery and burden and explored whether rural-urban disparities in caregiver outcomes differed by education. MATERIALS AND METHODS: Longitudinal data (baseline, 4-6 weeks, and 3 months) on caregivers of older adults (≥ 70) with advanced cancer were obtained from a multicenter geriatric assessment (GA) trial (ClinicalTrials.gov: NCT02107443). Rurality was determined based on 2010 Rural-Urban Commuting Area codes. Caregivers' education was categorized as ≥ some college vs ≤ high school. Caregiver outcomes included Ryff Environmental Mastery (scored 7-35) and Caregiver Reaction Assessment (including self-esteem, disrupted schedules, financial problems, lack of social support, and health problems; each scored 1-5). Separate linear mixed models with interaction term of education and rurality were performed. RESULTS: Of 414 caregivers, 64 (15.5%) were from rural areas and 263 (63.5%) completed ≥ some college. Rurality was significantly associated with more disrupted schedules (β = 0.21), financial problems (β = 0.17), and lack of social support (β = 0.11). A significant interaction between education and rurality was found, with rurality associated with lower mastery (β = -1.27) and more disrupted schedule (β = 0.25), financial problems (β = 0.33), and lack of social support (β = 0.32) among caregivers with education ≤ high school. CONCLUSION: Our study identifies subgroups of caregivers who are vulnerable to caregiving burden, specifically those from rural areas and with lower education. Multifaceted interventions are needed to improve caregivers' competency and reduce caregiving burden.