The purpose of this descriptive cross-sectional study was to explore the contribution of spiritual well-being and human immunodeficiency virus (HIV) symptoms to psychological well-being measured by depression, hope, and state-trait anxiety in a sample of 117 African-American men and women with a mean age of 38 years living with HIV disease. Of the respondents, 26% had acquired immunodeficiency syndrome (AIDS), and 74% were HIV seropositive. Each participant completed a sociodemographic questionnaire, the Sign and Symptom Checklist for Persons with HIV Disease, the Spiritual Well-Being Scale, the Nowotny Hope Scale, State-Trait Inventory, and the Beck Depression Inventory. The findings suggest that existential well-being, a spiritual indicator of meaning and purpose, more than religious well-being, was significantly related to the participants' psychological well-being. In addition, HIV symptoms were found to be significant predictors of psychological well-being. These findings support the need for nurses to continue exploring ways to integrate and support spirituality within the domains of clinical practice.