Objective: This study aimed to investigate the correlation of serum Jun-amino-terminal kinase (JNK) pathway-associated phosphatase (JKAP) level with disease risk, severity, inflammation, and treatment response to tumor necrosis factor (TNF)-alpha inhibitor in Crohn disease (CD) patients. Method: Ninety-six active CD patients and 90 healthy controls (HCs) were consecutively enrolled. Serum JKAP level of participants was determined via enzyme-linked immunosorbent assay (ELISA). In CD patients, C-reactive protein (CRP), erythrocyte sedimentation rate, Crohn disease activity index (CDAI), and inflammatory cytokine levels (determined by ELISA) were recorded. All CD patients underwent infliximab (IFX) treatment for 12 weeks, then treatment response (defined as decrement of CDAI >= 70) was assessed at week 12 (W12). Results: Serum JKAP level in CD patients was lower compared to HCs, and it disclosed a good predictive value for decreased CD risk; meanwhile, it was negatively correlated with CRP level, CDAI score, TNF-alpha, interleukin (IL)-6, and IL-17 levels in CD patients. Sixty-eight (70.8%) patients achieved treatment response to IFX at W12, and JKAP level was increased at W12 compared to baseline. Interestingly, baseline JKAP level in response patients was decreased compared to nonresponse patients, and it exhibited a good predictive value for decreased treatment response to IFX, multivariate logistic regression revealed that JKAP was an independent factor for predicting reduced IFX response. Conclusion: Circulating JKAP expression correlates with decreased disease risk, activity, and inflammation level, and it could be served as a novel biomarker for predicting reduced clinical response to TNF-alpha inhibitor in CD patients.