The insular cortex is a paralimbic area of the brain thought to have important roles in sensory integration, auditory hallucinations and language. Both structural and functional MRI studies have revealed that this brain area is abnormal in both size and activity in schizophrenia. Further investigation of this region at the cellular level in schizophrenia has not been carried out. In the current study, we conducted a stereological examination of neuronal and glial size and density in layers 2 and 3 of the dorso-caudal region of the insular cortex in 15 schizophrenic, 15 bipolar, 15 unipolar and 15 control patients. These cortical layers are candidate layers based on previous cytoarchitectual investigations. Statistical analysis (ANCOVA, correcting for pH, post-mortem interval and age) showed decreased neuronal volume in layer 2 in schizophrenia (p=0.0008, 16.2% mean reduction). No other significant changes were observed. This study thus provides the first evidence of cytoarchitectural abnormality of the insular cortex in the pathophysiology of schizophrenia but not mood disorders. Further work is needed to investigate the molecular basis for this neuronal abnormality in schizophrenia in order to elucidate its role in the pathophysiology of schizophrenia.