Background:Limited published data suggests that absence of uplifts (minor pleasant events) is associated with clinical worsening in patients with chronic fatigue syndrome (CFS). The current study aimed to assess the relation of illness worsening to the trajectories of social and non-social uplifts and hassles in a six-month prospective study in CFS.Methods:Participants were primarily in their 40s, female, white, and ill for over a decade. All participants (N=128) met criteria for CFS. The interview-based global impression of change rating was used to classify individual outcomes as improved, unchanged, or worsened at six- month follow-up. Uplifts and hassles, both social and non-social, were assessed with the Combined Hassles and Uplifts Scale (CHUS). The CHUS was administered weekly in online diaries over six months. Linear mixed effect models were utilized to examine linear trends for hassles and uplifts.Results:No significant differences were found between the three global outcome groups for age, sex, or illness duration; however, work status was significantly lower for the non-improved groups (p<.001). Non-social hassles intensity showed an increasing slope for the worsened group (p=.03) and a decreasing slope (p=0.05) for the improved group. For the worsened group, a downward trend was found for frequency of non-social (p=0.01) uplifts.Conclusion:Individuals with worsening as compared to improving illness in CFS show significantly different six-month trajectories for weekly hassles and a deficit in uplifts. This may have clinical implications for behavioral intervention.Trial Registration:ClinicalTrials.govID:NCT02948556