Schizophrenia is a major mental illness thought to result from disordered neurodevelopment. It is postulated that connectivity within brain systems controlling perception, language and cognition is disrupted. Using Diffusion Tensor Imaging (DTI) the integrity of white matter pathways in brain can be assessed. The directional diffusion of water molecules (fractional anisotrophy, FA) ranges from 0 (completely random) to 1 (completely isotrophic ­ in one direction) such that the more constrained movement is, say within a myelin sheath, the closer fractional anisotrophy is to 1. However, DTI studies in schizophrenia are confounded by medication effects and the duration of illness. To avoid these complications this study is one of the first to investigate FA indices of cerebral white matter connectivity in never-medicated individuals with first onset schizophrenia. White matter abnormalities in patients with schizophrenia were first compared to matched healthy subjects, and then correlations with illness severity examined. Twenty-five never-medicated patients with first episode schizophrenia and 24 healthy volunteers completed the study. The two groups did not significantly differ in age, sex ratio, handedness or ethnicity. Voxel-based analysis (VBA) was used to compare fractional anisotropy (FA) maps between the schizophrenia group and healthy controls. The VBA analyses were repeated with various sizes of smoothing kernel (4mm to 14mm) and with both parametric and non-parametric statistical approaches, in order to determine the most reliable result. A region of interest (ROI) analysis of FA scores was performed on 6 brain regions related to the significant group difference found in VBA, blind to group membership, to further assess validity of parametric and non-parametric methods. Results obtained consistently showed FA in the patients was not increased relative to healthy controls, but reduced in the right posterior limb of internal capsule, left middle temporal gyrus, right substantia nigra, left cerebral peduncle, and splenium of corpus callosum. Voxel-wise correlation analysis of the severity of positive and negative symptoms on the Positive and Negative Symptom Scale (PANSS) and FA in the patient group was performed. Selection of the most appropriate level of smoothing was based upon parametric VBA results from the group analysis. The results showed a significant positive correlation between positive symptom scores and FA values in bilateral medial frontal gyrus (left superior & right anterior region of coronal radiata), left cuneus (left posterior region of coronal radiata), left pre-central gyrus (superior occipitofrontal fasciculus), right body of cingculum, right medial orbital gyrus (inferior frontooccipital fasciculus/uncinate fasciculus), left superior longitudinal fasciculus near insular gyrus, and left superior temporal gyrus (inferior longitudinal fasciculs/inferior frontooccipital fasciculus). In conclusion, this is the first study to demonstrate that striato-limbic white matter dysconnectivity in schizophrenia is unrelated to treatment and illness chronicity. The use of FA as a useful marker for pathology in schizophrenia as well as its potential to assess response to neuroleptic treatment is discussed.