The purpose was to determine the minimally important clinical difference (MICD) in fatigue as measured by the Profile of Mood States, Schwartz Cancer Fatigue Scale (SCFS), General Fatigue Scale, and a 10-point single-item fatigue measure. The MICD is the smallest amount of change in a symptom (e.g., fatigue) measure that signifies an important change in that symptom. Subjects rated the degree of change in their fatigue over 2 days on a Global Rating Scale. 103 patients were enrolled on this multisite prospective repeated measures design. MICD was determined following established procedures at two time points. Statistically significant changes were observed for moderate and large changes in fatigue, but not for small changes. The scales were sensitive to increases in fatigue over time. The MICD, presented as mean change, for each scale and per item on each scale is: POMS = 5.6, per item = 1.1, SCFS = 5.0, per item = 0.8, GFS = 9.7, per item = 1.0, and the single item measure of fatigue was 2.4 points. This information may be useful in interpreting scale scores and planning studies using these measures.