Objective To explore the association between CpG island methylation in the promoter region of RELN and positive (type I) and negative (type II) types of schizophrenia, and investigate serum interleukin (IL)-1β, IL-6, and myelin basic protein (MBP) in schizophrenia. Methods Levels of CpG island methylation in the promoter region of RELN were detected in peripheral blood of patients with schizophrenia (experimental group) and healthy individuals (control group), and serum IL-1β, IL-6, and MBP were measured. Results The positive rate of CpG island methylation in the promoter region of RELN was higher in the experimental group than in the control group; however, there were no significant differences between type I and II patients. There were differences in Positive and Negative Syndrome Scale (PANSS) scores and serum IL-1β, IL-6, and MBP between type I and II patients. Furthermore, there were positive correlations between serum IL-1β, IL-6, and MBP and PANSS scores (negative symptoms) in type II patients. Conclusion CpG island methylation in the promoter region of RELN was associated with schizophrenia, but not with its clinical type. There may be different pathological mechanisms in type I and II schizophrenia, and type II schizophrenia may be associated with serum IL-1β, IL-6, and MBP.