Living with HIV involves management of multiple stressful disease-related and other life events. Distress tolerance may provide a functional, individual-based context for qualifying the established relationships between major life events and psychosocial variables important in the management of HIV. The present study provided a preliminary test of the hypothesis that distress tolerance moderates the impact of major life events on these predictors of disease progression. HIV-positive patients (n=116) completed psychosocial and medical questionnaires. Results indicated that major life events interacted with distress tolerance such that lower distress tolerance and higher life events were associated with significantly higher levels of depressive symptoms, substance use coping, alcohol and cocaine use, and medication adherence. In addition, distress tolerance was directly related to self-reported HIV-related symptoms. These results suggest that low distress tolerance, particularly in the face of major life events, may present significant challenges to adaptive management of HIV. Distress tolerance assessment may help to specify targets for cognitive-behavioral and stress management treatments for people living with HIV.