This investigation sought to determine the association of symptom distress with selected psychological factors in HIV-infected persons. Data from a randomized controlled trial were used; all subjects who completed baseline data collection were included (N = 99). Data packets included these questionnaires: the Perceived Stress Scale, HIV-related Symptom Distress Scale, and Profile of Mood State. Significant correlations were included in a final regression model. The Perceived Stress Scale, total mood disturbance (including the Profile of Mood State subscales), self-rated current health, and HIV status were independently associated with both frequency of symptoms and symptom distress. Symptom frequency, depression, anger, and fatigue retained significance in the final regression model. Findings from this study indicated significant associations of multiple psychological correlates, suggesting that symptom distress is a complex outcome with a multifactorial etiology. Psychological factors such as depression, anger, and fatigue contribute to the level of distress experienced with HIV-related symptoms.