The low density of cerebellar dopamine D2/D3 receptors provides the basis for using the cerebellum as a representation of free- and non-specifically bound radioligand in positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies. With the development of ultra high-affinity dopamine D2/D3 ligands like [123I]epidepride, [18F]fallypride, and [11C]FLB-457, quantification of extrastriatal low density receptor populations including the cerebellum is possible with important implications for calculation of binding parameters. [123I]epidepride-SPECT was performed in 23 patients with schizophrenia before and after 3 months of antipsychotic treatment with either risperidone (n=14) or zuclopenthixol (n=9). In the unblocked situation and partially blocked situation, the average distribution volumes were 5.2±1.3 mL/mL and 4.0±0.8 mL/mL, respectively. The paired distribution volumes were reduced by 22±15% (mean±SD) after antipsychotic treatment (p<0.0001, paired Student'st-test). From the paired distribution volumes in cerebellum and extrastriatal regions, the average distribution volume representing free and non-specifically bound [123I]epidepride was calculated to be 3.3±0.8 mL/mL. Both the % [123I]epidepride fraction of plasma radioactivity (p>0.76) and the plasma [123I]epidepride concentration (p>0.45) were unchanged after antipsychotic treatment (paired Student'st-test). These results strongly suggest the presence of “non-negligible” specific [123I]epidepride binding to dopamine D2/D3 receptors in the cerebellum. Using the cerebellum as a representation of free and non-specifically bound radioligand and neglecting the specifically bound component may lead to results that erroneously imply that antipsychotic drugs bind to extrastriatal dopamine D2/D3 receptors with a higher affinity than to striatal dopamine D2/D3 receptors.