OBJECTIVE: To examine the influence of incident stressful experiences on antiretroviral medication adherence and treatment outcomes. Past trauma history predicts poorer medication adherence and health outcomes. Human immunodeficiency virus (HIV)-infected individuals experience frequently traumatic and stressful events, such as sexual and physical assault, housing instability, and major financial, employment, and legal difficulties. METHODS: We measured prospectively incident stressful and traumatic events, medication adherence, and viral load over 27 months in an eight-site, five-state study. Using multivariable logistic and generalized estimating equation modeling, we assessed the impact of incident stressful events on 27-month changes in self-reported medication adherence and virologic failure (viral load = >or=400 c/mL). RESULTS: Of 474 participants on antiretroviral therapy at baseline, 289 persons were interviewed and still received treatment at 27 months. Participants experiencing the median number of incident stressful events (n = 9) had over twice the predicted odds (odds ratio = 2.32) of antiretroviral medication nonadherence at follow-up compared with those with no events. Stressful events also predicted increased odds of virologic failure during follow-up (odds ratio = 1.09 per event). CONCLUSIONS: Incident stressful events are exceedingly common in the lives of HIV-infected individuals and negatively affect antiretroviral medication adherence and treatment outcomes. Interventions to address stress and trauma are needed to improve HIV outcomes.