The Fatigue Symptom Inventory has been used extensively to assess and measure fatigue in a number of clinical populations. The purpose of the present study was to further establish its utility by examining its operating characteristics and determining the optimal cutoff score for identifying clinically meaningful fatigue. The MOS 36-Item Short Form Vitality scale, a measure widely used to identify individuals with significant fatigue-related disability, was used to determine the sensitivity and specificity of the Fatigue Symptom Inventory. Results indicate that a score of 3 or greater on those items assessing fatigue in the past week is the optimal cutoff score for identifying clinically meaningful fatigue. Individuals who scored at or above the cutoff also reported significantly greater fatigue interference, more days of fatigue on average, and fatigue a greater proportion of each day in the past week. Findings suggest that the Fatigue Symptom Inventory can be used to discriminate effectively between individuals with and without clinically meaningful fatigue.