BACKGROUND: Spirituality/religion is an important factor in health and illness, but more work is needed to determine its link to quality of life in patients with HIV/AIDS. OBJECTIVE: To estimate the direct and indirect effects of spirituality/religion on patients' perceptions of living with HIV/AIDS. DESIGN: In 2002 and 2003, as part of a multicenter longitudinal study of patients with HIV/AIDS, we collected extensive demographic, clinical, and behavioral data from chart review and patient interviews. We used logistic regression and path analysis combining logistic and ordinary least squares regression. SUBJECTS: Four hundred and fifty outpatients with HIV/AIDS from 4 sites in 3 cities. MEASURES: The dependent variable was whether patients felt that life had improved since being diagnosed with HIV/AIDS. Spirituality/ religion was assessed by using the Duke Religion Index, Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being - Expanded, and Brief RCOPE measures. Mediating factors included social support, self-esteem, healthy beliefs, and health status/health concerns. RESULTS: Approximately one-third of the patients felt that their life was better now than it was before being diagnosed with HIV/AIDS. A 1-SD increase in spirituality/religion was associated with a 68.50% increase in odds of feeling that life has improved - 29.97% due to a direct effect, and 38.54% due to indirect effects through healthy beliefs (29.15%) and health status/health concerns (9.39%). Healthy beliefs had the largest effect on feeling that life had improved; a 1-SD increase in healthy beliefs resulted in a 109.75% improvement in feeling that life changed. CONCLUSIONS: In patients with HIV/AIDS, the level of spirituality/religion is associated, both directly and indirectly, with feeling that life is better now than previously. Future research should validate our new conceptual model using other samples and longitudinal studies. Clinical education interventions should focus on raising awareness among clinicians about the importance of spirituality/religion in HIV/AIDS. © 2006 by the Society of General Internal Medicine. All rights reserved.