Background <p><i>Clostridioides difficile</i> infection (CDI) frequently occurs concurrently in patients with inflammatory bowel disease (IBD), and differential diagnosis from IBD flares is critical. However, clinical management of <i>C. difficile</i> in IBD patients with polymerase chain reaction toxin-positive (tPCR+)/enzyme immunoassay toxin-negative (tEIA−) results has not yet been investigated.</p> Aims <p>We aimed to assess the clinical significance of <i>C. difficile</i> tPCR+/tEIA− in patients with IBD and the impact of antibiotic treatment on IBD outcomes.</p> Methods <p>This single-center, retrospective cohort study included patients with IBD with CDI test results between January 01, 2018, and August 01, 2022. First, the clinical outcomes of IBD, such as medication escalation, hospitalization, and surgery, were compared between patients with IBD with tPCR−/tEIA− and those with tPCR+/tEIA− using Cox regression and propensity score matching. Next, the clinical outcomes of IBD were assessed based on whether antibiotic treatment for CDI was administered to both groups.</p> Results <p>Among 412 patients with IBD with PCR test, 71 (17.2%) showed tPCR+/tEIA− results. The tPCR+/tEIA− group showed no statistically significant difference in IBD outcomes compared to the tPCR−/tEIA− group. The antibiotic-treated tPCR+/tEIA− group showed a higher risk of drug escalation and admission than the tPCR−/tEIA− group, while the antibiotic-untreated tPCR+/tEIA− group did not. After drug escalation during the follow-up, the treated tPCR+/tEIA− group showed IBD outcomes similar to those of the tPCR−/tEIA− group.</p> Conclusions <p>In patients with IBD with indeterminate CDI, the need for antibiotics should be thoroughly assessed and proper management of underlying IBD such as drug escalation may lead to favorable outcomes.</p>