This cross-sectional survey study aimed to determine the effects of uncertainty on depression through the appraisal within the "uncertainty in illness" model. In 81 subjects with atrial fibrillation, individuals with greater symptom severity perceived more uncertainty. Uncertainty was appraised as a danger rather than an opportunity. While the appraisal of opportunity had a negative relationship with depression, the appraisal of danger was positively associated with depression. The indirect effect of uncertainty on depression through appraisal was supported by the empirical data on patients with atrial fibrillation. Helping patients to correctly interpret symptoms and to understand the effectiveness of treatment may modify and reduce their uncertainty so that uncertainty leading to worse health outcomes may be reduced.