Social isolation is an urgent threat to public health. Meanwhile, health outcomes across multiple measures are worse in rural areas, where distance to neighbors is often greater and opportunities for social interaction may be scarcer. Still, very little research examines rural-urban differences in social isolation. This study addresses that gap by examining differences in social isolation by rurality among US older adults. Using Wave 2 of the National Social Life, Health, and Aging Project data (n = 2,439), we measured differences between urban and rural (micropolitan or noncore) residents across multiple dimensions of social isolation. We also conducted multivariable analysis to assess the associations between rurality, sociodemographic characteristics, and loneliness, overall and by rurality. Finally, we conducted multivariable analysis to assess the association between social isolation and self-rated health, adjusting for rurality. Compared to urban residents, rural residents had more social relationships and micropolitan rural residents were more likely to be able to rely on family members (95.8% vs 91.3%, P < .05). Micropolitan rural residents reported lower rates of loneliness than urban residents after adjusting for sociodemographic and health characteristics (b = -0.32, P < .05), whereas noncore rural, non-Hispanic black residents had a greater likelihood of reporting loneliness (b = 4.33, P < .001). Overall, noncore and micropolitan rural residents reported less social isolation and more social relationships than urban residents. However, there were differences by race and ethnicity among rural residents in perceived loneliness. Policies and programs to address social isolation should be tailored by geography and should account for within-rural differences in risk factors. © 2019 National Rural Health Association.