This study examined the course of clinically significant cognitive change in hematopoietic stem cell transplant (HSCT), using a Reliable Change Index (RCI). Neuropsychological evaluations were administered to 117 patients before HSCT. Thirty-three received subsequent evaluations 6 and 28 weeks later. Of 117 patients, 39% were classified as impaired before HSCT. Of the 33 receiving subsequent evaluations, 47% showed reliable decline at 6-weeks; of these, 33% showed reliable decline again at 28-weeks. Mood and QOL did not account for declines. Verbal learning, psychomotor speed, and executive function showed greatest vulnerability to pre-HSCT impairment, and verbal learning showed greatest likelihood of further, subsequent decline. In conclusion, a subgroup of patients showed cognitive impairment before HSCT, indicating that factors other than HSCT contributed to cognitive deficits. Another subgroup showed further decline after HSCT. This study demonstrated the utility of the RCI in describing cognitive change in HSCT patients.