Abstract. Numerous studies have reported the aberrant expression profiles of microRNAs (miRNAs) in diffuse large B-cell lymphoma (DLBCL), although very few of these studies were concerned with chemoresistance to R-CHOP in DLBCL patients. This study was designed to assess the correlation between circulating miRNA expression and chemoresistance and prognosis in DLBCL patients. At the start of the study, we demonstrated that miRNA expression levels in serum were significantly associated with those in formalin-fixed, paraffin-embedded tissues, which indicated that circulating miRNAs may be powerful, non-invasive biomarkers reflecting miRNAs levels isolated from tumor tissue. Then from eight potential drug-resistant miRNAs which were deregulated in DLBCL and which had been reported to be associated with drug resistance in other carcinomas, we screened out the circulating miR-125b and miR-130a, which may related to R-CHOP resistance. Dynamic monitoring of the levels of circulating miR-125b and miR-130a further demonstrated that they were involved in recurrence, progression and chemoresistance in DLBCL patients. Finally, we demonstrated that high miR-125b indicated poor prognosis, as patients with higher miR-125b levels had a shorter overall survival. To our knowledge, this is the first study demonstrating that miR-125b and miR-130a are associated with the risk of chemoresistance in DLBCL patients, and that dynamic monitoring of the levels of circulating miR-125b and miR-130a predicts the therapeutic response and disease status of DLBCL patients.