Background: Few studies have investigated the role that spiritual activities play in the adaptational outcomes of women with human immunodeficiency virus (HIV) disease. Objective: To examine the role of spiritual activities as a resource that may reduce the negative effects of disease-related stressors on the adaptational outcomes in HIV-infected women. Methods: A theoretically based causal model was tested to examine the role of spiritual activities as a moderator of the impact of HIV-related stressors (functional impairment, work impairment, and HIV-related symptoms) on two stress-related adaptational outcomes (emotional distress and quality of life), using a clinic-based sample of 184 HIV-positive women. Results: Findings indicated that as spiritual activities increased, emotional distress decreased even when adjustments were made for HIV-related stressors. A positive relationship between spiritual activities and quality of life was found, which approached significance. Findings showed that HIV-related stressors have a significant negative effect on both emotional distress and quality of life. Conclusions: The findings support the hypothesis that spiritual activities are an important psychological resource accounting for individual variability in adjustment to the stressors associated with HIV disease.