BACKGROUND Psychological stress is thought to be an important factor in the pathogenesis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Therefore, we sought to examine this relationship in the context of parvovirus B19 infection. METHODS Thirty-nine patients with laboratory-documented acute parvovirus B19 infection were asked to complete questionnaires on negative life events, perceived stress, and negative affect relevant to the time of onset of parvovirus infection and during the preceding 12 months. These scores were combined into an overall stress index, which was then examined for associations with particular parvovirus-associated symptoms at acute infection and during the ensuing 1-3 years. Additional characteristics monitored included presence of parvovirus antibodies and nucleic acid, cortisol level, dehydroepiandrosterone level, autoantibodies, levels of a range of serum cytokines, and human leukocyte antigen class I and II alleles. RESULTS Stress index was significantly associated with development of fatigue during the acute phase of parvovirus B19 infection and also with chronic fatigue and arthritis occurring 1-3 years following acute parvovirus B19 infection. Logistic regression that included all clinical variables indicated that a high stress index at the time of onset of infection was the primary predictor of CFS/ME 1-3 years following acute parvovirus B19 infection (odds ratio, 25.7; 95% confidence interval, 1.7-121.9; P=.005). CONCLUSIONS We report a highly significant association between psychological stress and development of acute and chronic fatigue and arthritis several years following laboratory-documented acute parvovirus B19 infection.