Abstract: OBJECTIVE To investigate the effect of ziprasidone on the improvement of neuronal function and gray matter structure in patients with first-episode schizophrenia. METHODS A total of 92 adolescents with schizophrenia diagnosed as the psychiatric department from April 2017 to April 2018 were enrolled in Xuzhou Oriental People's Hospital. The patients were divided into two groups according to the random principle. The control group was only treated with psychotherapy in 46 cases. Forty-six patients were treated with oral ziprasidone for 6 months. The changes of serum neurocytokines, neurophysiological parameters and gray matter volume were compared before and after treatment. RESULTS There were no significant differences in GDNF, BDNF and other neurotrophic factors, P300, N2-P3 electrophysiological parameters between the two groups before treatment. The improvement to 4 indicators in the observation groups at 1st month and 2nd months of treatment compared with the control group(P<0.05). After 6 months, the volume of the right upper iliac crest and the right iliac crest was slightly increased from the observation group, and the difference was statistically significant(P<0.05). CONCLUSION Ziprasidone treatment of first-episode schizophrenia can effectively improve neuronal function, regulate neurophysiological function, alleviate the structural disorder of gray matter, and gradually restore the cognitive ability of patients.