Objective: To explore a potential role for spirituality in medication-related needs assessment for integrated care in chronically ill populations. Method: A systematic literature review was conducted to explore the impact of faith beliefs on health and/or medication adherence in individuals with depression and/or HIV+/AIDS. Retrospective electronic medical record review of adult HIV+ patients of an urban primary care clinic with integrated mental health services was conducted, with Substance Abuse and Mental Illness Symptoms Screener (SAMISS), major depressive disorder (MDD) incidence over the preceding year, and history of contact with a spiritual advisor. A convenience sample was interviewed to qualitatively assess potential medication therapy management needs and medication-related problems. Another sample was examined utilizing the Daily Spiritual Experience Scale. Results: The literature reports positive influence on health behaviors, coping and outcomes; and poor medication adherence and treatment decisions due to patient passivity or resistance. Spiritual advisor contact (not limited to a specific religion) was significantly associated with MDD absence (1.7% vs. 15.3%, P < 0.005) and inversely related to SAMISS, depression, and poor health behaviors. Patient interviews reflected significance of faith in terms of insight and acceptance of illness, the role or need for medications, coping, and medication adherence. An illustrative model was designed based on the literature and data collection. Conclusion: Spiritual assessment may help identify positive or negative influence on health. Spiritual interventions could be beneficial in promoting adherence and positive health outcomes. Further research is recommended.