Advances in antiretroviral therapies for HIV infection have given rise to new hope for the long-term survival of people living with HIV/AIDS. The current study examined changes in depression, anxiety, and HIV treatment attitudes that may co-occur with improvements and setbacks in HIV disease progression in a prospective cohort of 166 HIV-positive men and women. Results from a 9-month prospective observation period showed that persons who experienced increases in viral load, as indexed by medical chart abstraction, reported modest increases in depression and decreases in positive attitudes toward HIV treatments. Persons who experienced substantive decreases in viral load to undetectable levels demonstrated meaningful reductions in depression, particularly affective symptoms of depression after statistically controlling for years living with HIV, HIV symptoms, and age. Results suggest that emotional distress and perceptions of HIV treatments change in parallel to markers of HIV disease progression, especially with regard to reduced emotional distress in response to clinically significant changes in viral load.