Evidence so far indicates the consistent association between brain structural abnormalities and schizophrenia already present at the early phases of the illness. This study investigates the specificity of brain structural abnormalities in schizophrenia by using region-of-interest method of volumetric analysis in a heterogeneous sample of schizophrenia spectrum patients at their first break of the illness. 225 subjects, comprising 82 schizophrenia patients, 36 schizophreniform disorder patients and 24 patients with non-schizophrenic non-affective psychoses, and 83 healthy individuals underwent a magnetic resonance imaging brain scan. Quantitative brain morphometric variables were assessed: cortical CSF, lateral ventricle, total brain tissue, white matter and cortical and subcortical gray matter volumes. The contribution of sociodemographic, cognitive and clinical characteristics was controlled. Compared with controls, schizophrenia (P=0.017) and schizophreniform disorder (P=0.023) patients showed an increase in cortical CSF volume. Schizophrenia patients had also markedly enlarged lateral ventricle volume compared to controls (P=0.026). The patients with non-schizophrenic non-affective psychoses did not significantly differ in lateral ventricle and cortical CSF volumes from controls. Compared with controls, schizophrenia and schizophreniform disorder patients demonstrated a significant decrease in total brain tissue (-1.30% and -1.12% respectively). Thalamic volume was reduced (-3.84%) in schizophrenia patients compared to controls (P=0.040). Clinical and cognitive variables were not significantly related with morphological changes. The brain changes found in patients with a first episode of schizophrenia spectrum disorders are robustly associated with the diagnoses of schizophrenia and schizophreniform disorder and are independent of relevant intervening variables.