Although past work has documented relations between HIV/AIDS and negative affective symptoms and disorders, empirical work has only just begun to address explanatory processes that may underlie these associations. The current investigation sought to test the main and interactive effects of HIV symptom distress and anxiety sensitivity in relation to symptoms of panic disorder (PD), social anxiety disorder (SA), and depression among people with HIV/AIDS. Participants were 164 adults with HIV/AIDS (17.1% women; mean age, 48.40) recruited from AIDS service organizations (ASOs) in Vermont/New Hampshire and New York City. The sample identified as 40.9% white/Caucasian, 31.1% black, 22.0% Hispanic, and 6.1% mixed/other; with more than half (56.7%) reporting an annual income less than or equal to $10,000. Both men and women reported unprotected sex with men as the primary route of HIV transmission (64.4% and 50%, respectively). HIV symptom distress and anxiety sensitivity (AS) were significantly positively related to PD, SA, and depression symptoms. As predicted, there was a significant interaction between HIV symptom distress and anxiety sensitivity in terms of PD and SA symptoms, but not depressive symptoms. Results suggest that anxiety sensitivity and HIV symptom distress are clinically relevant factors to consider in terms of anxiety and depression among people living with HIV/AIDS. It may be important to evaluate these factors among patients with HIV/AIDS to identify individuals who may be at a particularly high risk for anxiety and depression problems. Limitations included recruitment from ASOs, cross-sectional self-report data, and lack of a clinical diagnostic assessment.