Aim <p>Schizophrenia is a chronic brain disorder with cognitive impairment as one of the cardinal manifestations. White matter organization abnormalities shown on brain imaging were also documented in patients with schizophrenia. However, when and how the cognitive impairment, the white matter organization abnormalities and their correlation occur and evolve throughout the illness course of schizophrenia remain undetermined. We aimed to show cognitive impairment and white matter organization abnormalities across different stages of schizophrenia and the association between them.</p> Methods <p>We collected 4 groups of participants: 40 individuals with illness duration of schizophrenia below 5 years, 36 individuals with illness duration of schizophrenia around 15 years, 39 individuals with illness duration of schizophrenia above 25 years, and 78 healthy controls. All participants underwent 3 cognitive tests (Wisconsin Card Sorting Test, Digit Span, Mini-Mental Status Examination) and 2 diffusion tensor imaging analyses of white matter (fractional anisotropy and graph theoretical analysis).</p> Results <p>We found cognitive impairment aggravated from early stage to the third decade of illness in schizophrenia. The associated white matter structural abnormalities had two steps of change: alteration in network organization occurred at early stage of schizophrenia, and then reduction in white matter tract integrity ensued from the second decade of the illness. The white matter integrity reduction was associated with cognitive impairment.</p> Conclusion <p>By using groups of participants with different illness duration, we found cognitive impairment and white matter organization abnormalities and their association across a three-decade illness course in schizophrenia. Our findings suggested active cognitive rehabilitation to patients with schizophrenia throughout the course of illness may be warranted.</p>