To investigate the degrees of EB virus reactivation in patients with inflammatory bowel disease (IBD) treated with different biologics and the levels of important cytokines associated with relapse under the influence of this virus, and to assess its diagnostic efficacy as a risk factor for identifying disease relapse. A case-control retrospective study based on patients' hospitalization history data was conducted to select a total of 105 patients who were hospitalized in the Department of Gastroenterology, Huashan Hospital, Fudan University, with a confirmed diagnosis of IBD from 2021 to 2023. Based on the quantitative copy level of whole blood EBV DNA to determine the status of EB virus infection in patients, integrated cytokine 8 (IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17, TNF-α, IFN-γ), C-reactive protein, and fecal calreticulin, to find the risk variable associated with treatment relapse. Logistic regression was used to analyze the relative risk between this variable and treatment relapse, and ROC curves were used to predict the diagnostic efficacy of cytokine multifactorial thresholds for treatment relapse. Results showed that the median age of the study was 37(26, 54)years, with a minimum of 18 years and a maximum of 70 years, with a median age of 34(24, 51) years for Crohn's Disease (CD) patients and 46(35, 60) years for Ulcerative colitis (UC) patients, with a statistically difference between the ages of the two groups (t=2.675, P=0.009). The median age at 50 years of patients treated with Vedolizumab (VDZ) in the UC group was higher than in the treatment groups other than VDZ. The highest rate of EB virusreactivation was found in the group treated with immunosuppressants Azathioprine (AZA) combined with anti-tumor necrosis factor-α (anti-TNF-α) and VDZ (62.5% in both groups), and the lowest in the group treated with Ustekinumab (UST) (0%). IL-2 levels were elevated in the AZA+anti-TNF-α and anti-TNF-α groups after EB virus entryreactivation. Three treatment groups, AZA+anti-TNF-α, anti-TNF-α, and VDZ, had elevated levels of IL-6 expression after EB virus entry reactivation.In the anti-TNF-α treatment-related group IL-2was associated with treatment relapse in IBD (OR=1.127, 95%CI: 1.044-1.256, P=0.007). ROC analysis showed that the AUC for IL-2 combined with EB virus in a replicative state was 0.8282 (P=0.006), with a negative predictive value and a positive value of 90% and 75%, respectively. As well as IL-6 was associated with treatment relapse of IBD in the anti-TNF-αtreatment-related group as well as in the VDZ-treated group (OR=1.049, 95%CI: 1.017-1.095, P=0.008). ROC analysis showed that the diagnostic sensitivity and specificity for post-treatment relapse at a critical value of 6.10 pg/ml for IL-6 was 83.33% and 82.93%, respectively. The AUC for IL-6 combined with EB virus in a replicative state was 0.900 (P<0.000 1), with negative and positive predictive value of 84.09% and 73.33%, respectively. In summary, the imbalance of proinflammatory and anti-inflammatory cytokines varies between drugs, with EBV in a replication-activated state, combined with elevated levels of IL-2 as well as IL-6 expression being a risk factor for relapse in patients treated with anti-TNF-α-related drugs and VDZ.