The objectives of the current study were to describe the development of a social isolation measure based on Berkman and Syme's Social Network Index domains with data from the National Health and Aging Trends Study. A descriptive correlational design was used, establishing convergent and divergent validity of the measure with depression risk and well-being. Depression risk was measured with the Patient Health Questionnaire-2 and an ordinal well-being measure was developed based on measures in MIDUS–Midlife in the U.S.–A Study of National Health and Well-Being. Participants who scored ≥4 (cutoff point) on the social isolation measure represented 21.9% ( N = 7,609) of the sample (95% confidence interval [20.6, 23.3]). Spearman's correlation with depression was 0.23 ( p < 0.001) and −0.24 ( p ≤ 0.001) with well-being. The weighted data complex samples general linear model with depression ( R = 0.22, p ≤ 0.001) and well-being ( R = −0.26, p ≤ 0.001) confirm the relationships. This measure offers conceptual clarity and measurement consistency for developing the components and targets for future social isolation intervention research. [Res Gerontol Nurs. 2017; 10(6):277–287.]