We examined prospectively the relationship between progressive disability in Huntington's disease (HD) and concomitant alterations in neuropsychological functioning and brain imaging indices in a cohort of 60 patients who were enrolled and followed for 30 to 42 months in a controlled clinical trial. Standardized measures of functional capacity and neuropsychological performance were collected, and CT was performed, at regular intervals every 6 to 12 months. Psychomotor skills showed the most significant and consistent decline among the cognitive functions assessed. Memory disturbances were already present at the time of enrollment, but memory did not deteriorate until patients reached advanced stages. Other cognitive operations, such as visual construction and semantic knowledge, manifested small and variable changes over time. CT indices of striatal atrophy correlated only with changes in psychomotor function, while the CT index of frontal atrophy weakly predicted memory and semantic knowledge scores at 42 months. These results confirmed earlier cross-sectional findings and extended our knowledge of the evolution of cognitive dysfunction in HD.