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Background and Aim Previous studies have shown differential TIPE2 expression in several autoimmune diseases. However, the expression levels of TIPE2 in primary biliary cirrhosis (PBC) remained unclear. The purposes of this study were to evaluate TIPE2 expression levels in patients with PBC and further investigate its role in PBC pathogenesis. Methods A total of 40 PBC patients and 44 healthy controls were included in the present study. Quantitative reverse-transcription polymerase chain reaction and western blotting were used to determine the differences in mRNA and protein expression levels of TIPE2. The correlations of TIPE2 expression levels and clinical characteristics, inflammatory cytokines, and ursodeoxycholic acid treatment were also assessed. Besides, the influence of TIPE2 on the reactivity of monocyte to Toll-like receptor ligands was further analyzed. Results The expression levels of TIPE2 were significantly decreased in PBC patients compared with normal controls ( P < 0.01). The expression levels of TIPE2 were negatively correlated with alanine aminotransferase ( r = −0.40, P = 0.01), alkaline phosphatase ( r = −0.36, P = 0.02), gamma glutamyl transpeptidase ( r = −0.53, P < 0.01), tumor necrosis factor (TNF)-α ( r = −0.332, P = 0.03), interleukin (IL)-1β ( r = −0.386, P = 0.01), and IL-8 ( r = −0.366, P = 0.02) levels in sera from PBC patients. TIPE2 expression level could be significantly increased after ursodeoxycholic acid treatment ( P < 0.01). The production of TNF-α, IL-1β, and IL-8 by monocytes from PBC patients after stimulation with lipopolysaccharide and lipoteichoic acid was significantly increased when TIPE2 was knocked down. Furthermore, TIPE2 knockdown could promote activation of nuclear factor-κB pathways through increasing phosphorylation and degradation of IκB in peripheral blood monocytes from PBC patients. Conclusion The present study reported that insufficient expression of TIPE2 might be involved in the hyperreactivity of monocyte to Toll-like receptor ligands in PBC. [ABSTRACT FROM AUTHOR]