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Studies suggest there is a high prevalence of burnout and depression among U.S. nurses.The aim of the study was to gauge the capability of the Well-Being Index (WBI) to stratify nurse distress (e.g., low quality of life [QOL], extreme fatigue, burnout, recent suicidal ideation) and well-being (high QOL) and detect those whose level of distress may negatively affect retention or work performance.In 2016, we conducted a cross-sectional survey of 3,147 U.S. nurses. The survey included the WBI and standard instruments to assess overall QOL, fatigue, burnout, recent suicidal ideation, patient care errors, and intent to leave current job. We used Fisher exact test and Wilcoxon/two-sample t-test procedures with a 5% Type I error rate and a two-sided alternative.Of the 812 (26%) nurses who completed the survey, 637 were eligible for the present analysis. Nurses with low mental QOL, extreme fatigue, recent suicidal ideation, or burnout had a higher total score (all ps < .001), resulting in less favorable WBI scores. With a 17% pretest probability of low overall QOL, the WBI score can decrease the posttest probability of low QOL to 2% or increase it to 72%. The likelihood of high overall QOL decreased in a stepwise fashion from 3.38 to 0.04, as the WBI score increased. WBI score also stratified nurses’ likelihood of reporting a recent patient care error and/or intent to leave current job.The WBI is a useful screening tool to stratify both distress and well-being across a variety of domains in nurses and identify those nurses whose severity of distress may negatively affect patient care and retention.