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The Disrupted-in-Schizophrenia 1 (DISC1) gene and negative symptoms in schizophrenia are both implicated in neurodevelopmental abnormalities. However, their relationship remains unclear. Thus, this study aimed to compare plasma DISC1 levels and negative symptoms severity between first-episode schizophrenia (FDS) patients and healthy controls (HCs), and examine their association. Sixty-six FDS patients meeting the DSM-IV diagnostic criteria, and 66 age- and sex-matched HCs were enrolled in this case-control study. Plasma DISC1 protein levels were measured by enzyme-linked immunosorbent assay (ELISA). Negative symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS). Compared to HCs, patients showed significantly higher CAINS scores for Motivation and Pleasure (MAP, F (1,130) = 5.24, p = 0.02), Expression (EXP, F (1, 130) = 33.89, p < 0.001), and total symptoms (F (1, 130) = 15.14, p < 0.001), alongside lower plasma DISC1 levels (F (1, 130) = 4.622, p = 0.034) after adjusting for convariates. Plasma DISC1 levels were negatively correlated with EXP score in patients (r = -0.30, p = 0.02), but not shown in HCs (r = -0.14, p = 0.26). Multiple linear regression identified lower plasma DISC1 levels as an independent predictor of higher EXP score in patients (β = -3.46, t = 2.23, p = 0.03), but not in HCs (β = 0.15, t = 0.29, p = 0.77). These findings suggest that reduced plasma DISC1 levels in FDS patients are significantly associated with greater expressive deficits, further supporting a potential role for DISC1 in the neurobiology of negative symptoms of schizophrenia.