Purpose To characterize disease burden and medication usage in rural and urban adults aged ≥85 years. Methods This is a secondary analysis of 5 years of longitudinal data starting in the year 2000 from 3 brain‐aging studies. Cohorts consisted of community‐dwelling adults: 1 rural cohort, the Klamath Exceptional Aging Project (KEAP), was compared to 2 urban cohorts, the Oregon Brain Aging Study (OBAS) and the Dementia Prevention study (DPS). In this analysis, 121 participants were included from OBAS/DPS and 175 participants were included from KEAP. Eligibility was determined based on age ≥85 years and having at least 2 follow‐up visits after the year 2000. Disease burden was measured by the Modified Cumulative Illness Rating Scale (MCIRS), with higher values representing more disease. Medication usage was measured by the estimated mean number of medications used by each cohort. Findings Rural participants had significantly higher disease burden as measured by MCIRS, 23.0 (95% CI: 22.3‐23.6), than urban participants, 21.0 (95% CI: 20.2‐21.7), at baseline. The rate of disease accumulation was a 0.2 increase in MCIRS per year (95% CI: 0.05‐0.34) in the rural population. Rural participants used a higher mean number of medications, 5.5 (95% CI: 4.8‐6.1), than urban participants, 3.7 (95% CI: 3.1‐4.2), at baseline (P < .0001). Conclusions These data suggest that rural and urban Oregonians aged ≥85 years may differ by disease burden and medication usage. Future research should identify opportunities to improve health care for older adults.