This three-year longitudinal study assessed the association between social relationships and human immunodeficiency virus (HIV) progression in individuals at risk for morbidity and mortality due to acquired immune deficiency syndrome (AIDS). Two-hundred five HIV seropositive men without AIDS completed measures of social integration and loneliness at baseline. Blood samples used to assess CD4 T-lymphocyte levels were collected at baseline and at six-month intervals for a three-year follow-up period. Contrary to expectation, lower levels of baseline loneliness predicted more rapid declines in CD4 levels over the follow-up period. This association was independent of baseline CD4 values, negative affect, and health practices. A series of mediational analyses revealed that sexual behavior, medication use, bereavement, coping, and a number of other variables were not mechanisms through which loneliness affected the immune system. Loneliness was not associated with time to AIDS diagnosis or time to AIDS-related mortality. These findings are consistent with the emerging view that social relationships can have deleterious, as well as protective, influences on health outcomes.