The clinical features of schizophrenia can be mainly divided into two symptom domains: positive and negative. Patients in each symptom domain respond differently to treatments, and their prognoses vary accordingly. Serum protein factors, such as nerve growth factor (NGF), neurotrophin-3 (NT-3), interleukin-6 (IL-6), interleukin-1beta (IL-1β), and the calcium-binding protein S100β, have been reported to be involved in the pathogenesis of schizophrenia. However, their roles in the positive and negative symptom domains have not been determined. In this study, we investigated whether the serum levels of these five protein factors differed among first-episode drug-naïve schizophrenia patients in each symptom domain and healthy controls. Double-antibody sandwich enzyme-linked immunosorbent assays (ELISAs) were used to quantify the amounts of the five protein factors in serum. Compared with the levels in the controls (n = 60), increased serum levels of IL-6, IL-1β and S100β and decreased serum levels of NGF and NT-3 were observed in first-episode drug-naïve schizophrenia patients. Additionally, the serum levels of IL-6 and IL-1β were significantly higher in schizophrenia patients characterized by negative symptoms (negative group, n = 37) than in those characterized by positive symptoms (positive group, n = 46). Based on multivariate regression analyses, serum levels of IL-1β were positively associated with the negative symptom subscore of the Positive and Negative Syndrome Scale (PANSS) in the negative group and in all patients with schizophrenia. The two subtypes of schizophrenia may have different pathological mechanisms. Patients characterized by negative symptoms probably have more serious disturbances in neuroimmunology. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.