Background: The literature speculates that there may be a relationship between cognitive capacities and levels of fatigue in people with multiple sclerosis (MS), which has been under reported. This study has investigated one aspect of cognition by evaluating the association between problem-solving ability and the severity of fatigue. Methods: A cross-sectional, descriptive study was used to investigate the association between levels of problem-solving ability and degrees of fatigue severity. Eighty-five participants living in the city of Shiraz, Iran, completed Cassidy Problem-Solving Inventory (PSI) and the Fatigue Severity Scale (FSS). Pearson’ s Product Moment Correlation Coefficient was used to analyze the data. Results: Problem-solving was inversely associated with fatigue (r =-0. 381, P = 0. 009), whereby higher levels of problem-solving ability were associated with lower degrees of fatigue. Conclusion: The results of this study contributed to the ongoing debate about the linkage between cognition and fatigue in people with MS, suggesting an association between problem-solving ability and fatigue severity. A possible implication would be the importance of problem-solving training for people with MS.