To calculate binding potentials (BP) in brain PET studies a reference tissue model is widely used. The aim of the present study was to improve the determination of time activity curves (TAC) of reference tissue regions using cluster analysis. In four patients with Huntington disease TACs of a cerebellar reference region were calculated either from manually placed circular ROIs within the cerebellum or by cluster analysis. BP estimates derived from cluster analysis are independent from inter- and intraobserver variations and show an improved reproducibility combined with a low variability compared to manually placed cerebellar ROIs. This is of high value in longitudinal studies.