Background The apolipoprotein E (ApoE) gene polymorphisms are correlated with blood lipid levels and several neuropsychiatric symptoms. Therefore, this study aimed to examine whether the ApoE rs429358 affected the development and clinical symptoms of schizophrenia and to explore the relationship between apolipoproteins levels and clinical symptoms. Methods The ApoE rs429358 was genotyped using a case-control design. The Positive and Negative Syndrome Scale (PANSS) was employed to evaluate the psychopathology of all patients. Results A total of 637 patients with schizophrenia and 467 healthy controls were recruited. We found no significant differences in the genotype and allele distribution between the patient and control groups. A significant correlation between PANSS negative symptoms and ApoA1 levels (p = 0.048) or ApoB levels (p = 0.001) was found in patients with schizophrenia, which was also confirmed by linear regression analyses (p = 0.048 vs. p = 0.001). Interestingly, only in the T homozygote group, ApoA1 and ApoB levels were predictors of the PANSS negative symptom score (p = 0.008 vs. p = 0.012), while in the C allele carrier group, no correlation was observed. Conclusions This study found that the levels of ApoA1 and ApoB were negatively associated with negative symptoms of patients with schizophrenia. Furthermore, the association between ApoA1 or ApoB levels and psychopathology of schizophrenia was regulated by ApoE rs429358.