Abnormal keratinocyte terminal differentiation is one of the important characteristics of psoriatic lesions. Filaggrin (FLG) is a key protein that facilitates the terminal differentiation of the epidermis. Thus, FLG genetic variants may modify the risk of psoriasis. In total, 314 patients with psoriasis and 611 control subjects were analyzed for the presence of FLG R501X, 2282del4 mutations, and P478S (rs11584340, C/T base change) polymorphism by polymerase chain reaction (PCR). The analysis revealed that both the R501X and 2282del4 mutations were not present in a subset of 200 patients (64%) with psoriasis. In contrast, a marginally significant difference (P = 0.020) was found in the distribution of rs11584340 genotype frequencies between psoriatic patients and controls. The frequency of the TT genotype in psoriasis patients was significantly higher than in controls (37.9% vs. 29.1%, respectively, P = 0.007). The T allele frequency of patients (60.5%) was also significantly higher than that of controls (53.9%) (P = 0.007). After adjusting for age and gender, carriers of the TT genotype were 1.46 (95% CI, 1.08-1.96) times more likely than non-carriers to have psoriasis (P = 0.013). In conclusion, our results suggest that FLG P478S polymorphism may confer susceptibility to the development of psoriasis among Taiwanese Chinese.