Neuregulin 4 (Nrg4) has been proposed to play a role in the pathogeneses of obesity, insulin resistance, and dyslipidemia. However, information about the link between Nrg4 and metabolic syndrome (MetS) is scarce, especially in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). This study aimed at investigating whether Nrg4 is associated with MetS in nT2DM patients. A total of 311 patients with nT2DM were recruited. Plasma Nrg4 concentration was determined by ELISA. Plasma Nrg4 concentration was lower in nT2DM patients with MetS than in nT2DM patients without MetS (P = 0.001). Nrg4 concentration showed negative correlations with most of the analyzed indicators of MetS. MetS was less prevalent among subjects in the highest quartile of plasma Nrg4 concentration than among those in the lowest quartile (P < 0.01). Age- and sex-adjusted plasma Nrg4 concentrations were positively correlated with concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A (both P < 0.05) and negatively correlated with triglyceride, high-sensitivity C-reactive protein (hs-CRP), and gamma-glutamyltransferase concentrations, neutrophil count, and white blood cell (WBC) count (all P < 0.05). In multivariate analysis, Nrg4 was independently associated with hs-CRP level, WBC count, and HDL-C level (P = 0.001 or P < 0.05). Multiple logistic regression analysis of MetS prediction by Nrg4 revealed an odds ratio of 0.560 (95% CI: 0.374-0.837; P < 0.01). Decreased plasma Nrg4 levels, which may be associated with augmented oxidative stress, inflammation, and dyslipidemia, might be involved in the development of MetS in nT2DM patients.