Cell division cycle 42 (CDC42) participates in the pathogenesis of some T-cell-mediated inflammatory diseases via regulating CD4+ T-cell differentiation and inflammation response. This study aimed to evaluate the correlation of CDC42 and T helper (Th)1/Th2 cytokines with disease risk, effusion viscosity, and hearing loss degree of otitis media with effusion (OME). CDC42, interleukin (IL)-4, and interferon-gamma (IFN-γ) in effusion and serum of 78 OME patients were determined by enzyme-linked immunosorbent assay. Besides, the effusion (irrigating fluid) and serum samples of 30 controls (adenoid hypertrophy patients without OME) were also obtained for CDC42, IL-4, and IFN-γ determination. Effusion CDC42 and IL-4 were elevated in OME patients compared with controls (both p < 0.001). Effusion CDC42 was positively correlated with effusion IL-4 in OME patients (p=0.004) and controls (p=0.012) but was not related to effusion IFN-γ (both p > 0.050). Additionally, effusion CDC42 (p=0.025) and IL-4 (p=0.023) were increased in OME patients with mucoid effusion compared to patients with serous effusion, while effusion IFN-γ was of no difference between those patients (p=0.215). Meanwhile, elevated effusion CDC42 (p=0.012) and IL-4 (p=0.033) were linked with increased hearing loss degrees, whereas effusion IFN-γ was not related to hearing loss degrees (p=0.057). Moreover, the findings of serum CDC42, IL-4, and IFN-γ showed similar trends as effusion ones; nonetheless, their correlation with disease features was generally weaker. OME patients present with elevated CDC42 and IL-4 levels; the latter factors are intercorrelated and positively associate with effusion viscosity and hearing loss degree.