Discourse on deaths of despair, which include suicide, poisoning, and chronic liver disease, has focused on middle-aged White working-class adults with less than a college education. Yet longitudinal research has not examined what groups are at highest risk for these causes of death. Respondents to the 2008 American Community Survey were followed through 2015 for mortality from suicide, poisoning, or chronic liver disease. The overall mortality rate for deaths of despair was 41.3 per 100,000 person-years. The highest-risk groups were adults with functional disabilities (102.8 per 100,000 person-years), American Indian/Alaska Native people (102.6), working-age adults who are not employed (77.3), separated or divorced people (76.5), people with net income losses (70.6), and people with military service (67.0). Most of these groups remained at increased risk after several potential confounders were controlled for. These findings offer a deeper perspective on which adults are at highest risk for deaths of despair.