The relationship between serum BDNF levels and cognitive dysfunction in schizophrenia (SCZ) patients comorbid with type 2 diabetes mellitus (T2DM) has not been reported. Hence, this study aimed to explore whether and how the changes of serum BDNF levels were correlated with cognitive impairment in SCZ patients comorbid with T2DM. We recruited 472 inpatients with chronic SCZ (54 T2DM and 418 non-T2DM), and 225 healthy controls. Serum BDNF levels and routine biochemical parameters were measured. Psychopathological symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS) and cognitive function was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). SCZ patients with T2DM had significantly higher serum BDNF levels than SCZ patients without T2DM (F = 11.31, p = 0.001). SCZ patients with T2DM scored higher in delayed memory than SCZ patients without T2DM (77.17 +/- 18.44 vs.66.24 +/- 19.51, p = 0.000), and still showed significance after controlling for confounders. Further stepwise multiple regression analysis identified serum BDNF as an independent contributor to the RBANS attention of SCZ patients with T2DM (beta = 0.30, t = 2.09, p = 0.042). The increase of BDNF levels and better cognitive performance, especially delayed memory, may be related to the pathophysiological process of T2DM in chronic SCZ patients.