OBJECTIVES: The goals of this pilot cross-sectional study were to determine the feasibility of and begin measuring the effect of religious institution affiliation on human immunodeficiency virus (HIV) clinical outcomes in the southern United States, a region marked by later initiation of antiretroviral therapy, higher HIV-related morbidity, and higher mortality rates than people living with HIV (PLWH) elsewhere in the country. It also is a region with a high density of religious institutions, which may facilitate improved health outcomes through leveraged social capital. Because spirituality is a personal construct and PLWH constitute a vulnerable population, we wanted to determine whether it would be feasible to survey patients about the topic. We hypothesized that PLWH would be willing to participate and that PLWH who report involvement in religious institutions would be more likely to have suppressed HIV viral loads (VLs) and better engagement in care than PLWH not involved in a religious institution. METHODS: Eligible participants were enrolled from the Wake Forest Infectious Diseases Specialty Clinic to complete structured interviews using validated measures of religious institution affiliation, spiritual well-being, social support, and HIV-related stigma. HIV VL and engagement in care (clinic no-show rate) data were abstracted from the electronic medical record. Descriptive statistics calculated the prevalence of religious institution involvement, outcomes of interest, and potential confounders. Tests compared continuous outcomes assuming normality, χ tests compared binary outcomes, and the Wilcoxon Mann-Whitney test compared outcomes for non-normal data. RESULTS: Fifty participants completed the study (55% participation rate); 72% identified as male and 28% identified as female. A total of 48% of participants identified as black/African American and 44% identified as white. Participants who identified as men who have sex with men made up 34%. More black/African American participants than white participants reported religious institution affiliation (23%; = 0.15). There was no statistically significant relation between religious institution affiliation and CD4 or VL; however, higher levels of social support and spiritual well-being predicted a lower clinic no-show rate ( = 0.0077 and 0.0195, respectively). There was a trend toward greater perceived HIV-related stigma and CD4 ( = 0.0845) as well as more emergency department visits ( = 0.0976). CONCLUSION: PLWH in a southern US clinic were willing to answer questions about their spirituality. Religious institution affiliation was not significantly related to virologic suppression or CD4 in this sample. Higher levels of self-reported social support ( = 0.0077) and spiritual well-being ( = 0.0195) predict better clinic attendance. These results suggest that religious affiliation alone does not imply positive benefits for all. Social support and spiritual well-being, however obtained, predict engagement in care. The next steps should include a fully powered study to define the relations among social support, spiritual well-being, and relevant clinical outcomes. Our results also support further investigation of perceived HIV-related stigma and healthcare utilization, based on the trend toward significance between emergency department visits and stigma.