There has been evidence that the disturbances of TNF-α and the oxidative stress (OxS) status are involved in the mechanism of schizophrenia. However, the results of their levels in schizophrenia are still controversial, and their interactions have not yet been examined, especially in first-episode drug-naïve (FEDN) patients. We therefore applied Enzyme-linked immunosorbent assays (ELISAs) method to compare peripheral blood serum TNF-α, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) levels in 119 FEDN patients with schizophrenia and 135 healthy controls. We found that TNF-α and MDA were higher, whereas GSH-Px was lower, in FEDN patients with schizophrenia compared to healthy controls (TNF-α, 2.21 ± 0.33 vs. 2.11 ± 0.36, Bonferroni p = 0.04; MDA, 2.95 ± 0.87 vs. 2.68 ± 0.76, Bonferroni p = 0.04, GSH-Px, 177.33 ± 28.84 vs. 188.32 ± 29.34, Bonferroni p = 0.03). Furthermore, TNF-α levels had an independent positive association with negative symptoms (r = 0.37, Bonferroni p < 0.001). Finally, GSH-Px levels were negatively associated with the presence of schizophrenia (B =-0.014, Wald statistic = 9.22, p = 0.002, 95 %CI = 0.97-0.99), while the interaction of TNF-α with MDA was a risk factor for schizophrenia (B = 0.22, Wald statistic = 10.06, p = 0.002, 95 %CI = 1.09-1.43). Our results suggest that TNF-α and disturbance of oxidative stress status as well as their interaction may be involved in the pathophysiology of schizophrenia.Copyright © 2020 Elsevier Ltd. All rights reserved.