The effects of fatigue on neuropsychological performance were examined in patients with fatiguing illnesses. Repeated testing with the Paced Auditory Serial Addition Test (PASAT; Gronwall, 1977) was employed over the course of a demanding neuropsychological testing session. It was hypothesized that if fatigue affects performance, one would expect to observe "blunting" of the PASAT practice effect. Fifteen of the study participants live with chronic fatigue syndrome (CFS), 15 with multiple sclerosis (MS), 14 with depression (DEP), and 15 are healthy, sedentary controls. Overall PASAT performance was significantly reduced for CFS and DEP participants compared to controls, whereas mean performance did not differ across the three fatiguing illness groups. Degree of improvement across trials (i.e., practice effect) for the groups did not differ from controls'. Neither subjective fatigue or DEP were significantly related to PASAT performance. These findings suggest that fatigue does not universally impair performance during neuropsychological assessment even in groups in which fatigue is a prominent symptom.