We identified trajectories of illness uncertainty in chronic hepatitis C patients and examined their association with fatigue levels during 12 months of disease monitoring without treatment (watchful waiting). Sixty-two men and 63 women completed uncertainty and fatigue measures. Groups were formed by uncertainty scores (high, medium, and low) at baseline. Baseline fatigue levels were higher in the high uncertainty group than in the medium and low groups. Over time, uncertainty levels did not change. Fatigue levels in the low uncertainty group remained constant, increased in the medium, and decreased in the high groups. Findings suggest that uncertainty and fatigue do not remit spontaneously. Being aware of this may help nurses identify those patients needing support for these two concerns.