Objective To investigate the expression and clinical significance of microrNA-146B-5P in exosomes derived from serum and blister fluid of patients with bullous pemphigoid (BP).Methods Seventy-nine BP patients admitted to our hospital from June 2019 to December 2021 were selected as the study group. In addition, 61 healthy people undergoing health checkup in our hospital during the same period were selected as the control group. The basic data and biochemical indicators of the two groups were collected. The expression of microrNA-146B-5p was determined by quantitative real-time polymerase chain reaction. Multivariable Logistic regression analysis was performed to determine the factors affecting the diagnosis of BP. The receiver operating characteristic (ROC) curve was used to analyze the value of serum exosomal microrNA-146B-5p in the early diagnosis of BP. Pearson method was applied to analyze the correlation between the expression of exosomal microrNA-146B-5p in serum and blister fluid of BP patients and the severity of the disease.Results There was no difference in the sex composition, age, the proportion of patients with body mass index ≥ 25 kg/m², the proportions of patients with combined hypertension, diabetes mellitus, hyperlipidemia, and coronary heart disease, the proportions of patients with a history of smoking and alcohol consumption, the levels of serum creatinine, blood uric acid, alanine aminotransferase, aspartate aminotransferase, total bilirubin, hemoglobin, and albumin, white blood cell count, platelet count, and the levels of procalcitonin, tumor necrosis factor-α, CD14⁺ T cells, CD8⁺ T cells, interleukin (IL)-6, IL-4, IL-21 and 25-hydroxyvitamin D between the two groups (P > 0.05). The levels of C-reactive proteins, OX40, OX40L, macrophage migration inhibitor factor, eosinophil cationic protein (ECP), and serum exosomal microRNA-146b-5p in the study group were higher than those in the control group, whereas the level of CD4⁺ T cells in the study group was lower than that in the control group. Multivariable stepwise Logistic regression analysis showed that the relative expression of microrNA-146B-5P in serum exosomes [O^R = 5.191, (95% CI: 2.136, 12.617) ], the level of CD4⁺ T lymphocytes [O^R = 4.894, (95% CI: 2.014, 11.894) ] and the level of ECP [O^R = 4.076, (95% CI: 1.677, 9.905) ] were factors affecting the diagnosis of BP (P < 0.05). The ROC curve analysis demonstrated that the optimal cut-off value of the relative expression of serum exosomal microrNA-146B-5p for diagnosing BP was 1.11, with the sensitivity being 73.42% (95% CI: 62.09%, 82.44%), the specificity being 80.33% (95% CI: 67.78%, 89.00%), and the area under the ROC curve being 0.766 (95% CI: 0.671, 0.861). Pearson correlation analysis revealed that the levels of microrNA-146B-5P in blister fluid and serum were both positively correlated with the Bullous Pemphigoid Disease Area Index (BPDAI) score of BP patients (r = 0.741 and 0.736, all P < 0.05).Conclusions Exosomal microrNA-146B-5p is not only related to the occurrence of BP, but also may be related to the progression of the disease. The relative expression of serum exosomal microrNA-146B-5P is valuable in diagnosing BP.