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Boks MPM, Liddle PF, Burgerhof JGM, Knegtering R, van den Bosch R-J. Neurological soft signs discriminating mood disorders from first episode schizophrenia. Acta Psychiatr Scand 2004: 110: 29–35. © Blackwell Munksgaard 2004. To investigate the specificity of neurological soft signs (NSS) for first episode schizophrenia compared with mood disorders. We assessed NSS in a sample of 60 healthy controls, 191 first episode psychosis patients and 81 mood disorder patients. We used a principle component analysis to identify dimensions of NSS. We subsequently investigated the specificity of these dimensions for schizophrenia and their relationships with medication and symptom scores. We identified five dimensions; coordination disorders, movement disorders, increased reflexes, dyskinesia and catatonia. These dimensions were related to neural circuits associated with schizophrenia and mood disorders and included the fronto-striatal-thalamic and the fronto-cerebellar pathway. The movement disorder dimension, which was suggestive for the involvement of the fronto-striatal-thalamic pathway, was specific for first episode schizophrenia independent from medication. NSS are the result of circuitry dysfunctions rather than overall dysfunction and a particular set of NSS shows specificity for schizophrenia. [ABSTRACT FROM AUTHOR]