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Chronic fatigue syndrome (CFS) and unexplained chronic fatigue (CF) are characterized by compromised functional status and physical disability. Prior research on chronic pain has suggested that social factors may contribute to disability. This study examined the relationship between significant other responses and patient outcomes in patients with unexplained CF. Questionnaire data were collected from 117 patients on physical function, fatigue, pain, illness behaviors and responses of significant others to them, and depression. Ninety-four SOs reported their perceptions of patient illness behavior and their responses. Thirty-seven of these dyads also completed a series of household activities while being videotaped. Dyadic interactions were coded and analyzed. Both reported and observed solicitous responses by the significant other were associated with reported and observed patient illness behavior. Negative responses to patient illness behavior by significant others were associated with higher levels of patient depressive symptoms. The findings provide support for the role of operant behavioral factors in the context of chronic fatigue. They also suggest that further research on the relationship between dysfunction and significant other responses in patients with CFS or CF appears warranted and may have implications for treatment development.