Cytokines have an important role in the pathogenesis and disease progression of oral lichen planus (OLP). The aim of this study was to investigate the impact of gene polymorphisms of T helper cell subtype Th1 and Th2 cytokines, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), on OLP in an ethnic Chinese cohort. We investigated IFN-gamma gene (IFNG) and IL-4 gene (IL-4) polymorphisms in 151 patients with OLP and 143 healthy controls using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. Each genotype was also validated by direct DNA sequencing methods to further guarantee the significance of our findings. The data revealed that there were highly significant increases in +874 IFNG2 genotype distributions and allele T frequencies in both the OLP patient group (p = 0.033, 0.003) and the more progressive subtype group (eOLP)(p = 0.013, 0.001) compared with those of normal controls There was no difference between the OLP patient and healthy control groups in frequencies of both the IL-4 allele (p = 0.053) and genotype (p = 0.197), although the frequencies of the IL4-590 C allele (p = 0.001) and the CC genotype (p = 0.024) in patients with nonerosive OLP (neOLP) were significantly greater than the corresponding values in the control group. Our study suggests that IFN-gamma and IL-4 gene polymorphisms seem to have a positive influence on disease susceptibility and progression of OLP in this ethnic Chinese cohort.