Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain condition poorly understood in terms of etiology and treatment by both physicians and patients. This condition of “uncertainty of illness” was examined as a variable involved in the adjustment of FMS patients, relating it to their depression, anxiety, affect, and coping styles. Fifty-one community-residing FMS patients provided self-report information on subsets of adjustment variables. Both cross-sectional and more dynamic longitudinal analyses showed that illness uncertainty was significantly associated with anxiety, negative affect, and avoidant and passive coping. Its positive relationship with depression was eliminated when a control variable, pain helplessness, was included as a covariate. Longitudinally, illness uncertainty interacted with interpersonally stressful daily events in predicting reports of reduced positive affect, suggesting that illness uncertainty acts as a risk factor for affective disturbances during stressful times. Implications of these results for therapeutic interventions are discussed.