Background Little research on symptom impairment and quality of life among HIV-positive (HIV+) individuals has attended to the potential role of cognitive-affective vulnerabilities. Emerging research indicates that emotion regulation (ER), anxiety sensitivity (AS), and distress tolerance (DT) are associated with a range of mental health outcomes and demonstrate meaningful relations to clinical outcomes in HIV+ individuals. Purpose In this investigation, we sought to concurrently examine these factors in relation HIV symptom severity, barriers to medication adherence, and disease viral load. Method Participants were 139 HIV+ individuals (34 female; age M=48.2 years, SD=8.1, 42 % Black) receiving outpatient HIV care and prescribed at least one antiretroviral medication.We used hierarchical regression analyses to concurrently examine ER, AS, and DT in relation to severity of HIV symptoms, barriers to medication adherence, and disease viral load. Results After accounting for alcohol use problems, cannabis dependence, gender, and education, AS was significantly associated with HIV symptom severity (β = .35, p <.01) whereas ER evidenced a trend relation (β=.19, p=.07). ER (β=.45, p<.01), but not AS or DT, was significantly related to barriers to medication adherence, above and beyond variance accounted for by covariates. Finally, ER evidenced a trend level relation to viral load (β=.21, p=.07), above and beyond variance accounted for by cannabis use. Conclusion Findings provide an extension of previous research, suggesting unique roles of cognitive-affective vulnerabilities in terms of HIV symptom severity, medication use barriers, and infection symptomatology, and inform the refinement of current treatments for HIV+ individuals so as to improve functioning.