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Objective: Several studies have shown that rituximab may enhance hepatitis C virus (HCV) activity. MicroRNAs (miRNAs) have been implicated in modulating the host immune response in HCV infection; miRNAs can be packaged into the exosomes and then shuttled by the exosomes to aid biologic functions. However, the role of exosomal miRNAs (exo‐miRNAs) in rituximab‐related HCV activity enhancement remains unclear. Methods: The association between rituximab and increased HCV activity was examined using an in vitro cell‐based assay. Purified exosomes were confirmed using immunoblotting and flow cytometry and quantified using enzyme‐linked immunosorbent assay. Exosomal miRNA‐155 (exo‐miR‐155) levels were measured using quantitative reverse transcription–polymerase chain reaction. Results: In vitro data showed that B cell–derived miR‐155 could inhibit HCV replication in hepatocytes through exosome transmission. Rituximab could both induce B cell depletion and affect intracellular miR‐155 production as well as exo‐miR‐155 transmission and then enhance HCV activity in hepatocytes (P < 0.005). Serum exosome levels were increased in rheumatoid arthritis (RA) patients with HCV infection compared with the levels in RA patients without HCV infection (P < 0.01). The exo‐miR‐155 levels were significantly increased in RA patients with HCV infection compared with those without infection (P < 0.01). A significantly greater decrement of exo‐miR‐155 expression was observed after rituximab therapy compared with those observed before therapy (P < 0.01), and hepatitis C viral loads increased simultaneously (P < 0.05). Conclusion: Circulating exo‐miR‐155 levels were negatively correlated with hepatitis C viral loads and subsequently associated with rituximab‐related HCV activity enhancement in RA patients. Exo‐miR‐155 may become a potential diagnostic biomarker or therapeutic target. [ABSTRACT FROM AUTHOR]