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B cells play a central role in antibody‐mediated rejection and certain autoimmune diseases. However, B cell–targeted therapy such as anti‐CD20 B cell–depleting antibody (aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B cell reconstitution leading to aCD20 depletion resistance could account for these discrepancies. Using a transplantation model, we found that antigen‐independent inflammation, likely through toll‐like receptor (TLR)signaling, was sufficient to mitigate B cell depletion. Secondary lymphoid organs had a quicker recovery of B cells when compared to peripheral blood. Inflammation altered the pharmacokinetics (PK) and pharmacodynamics (PD) of aCD20 therapy by shortening drug half‐life and accelerating the reconstitution of the peripheral B cell pool by bone marrow–derived B cell precursors. IVIG(intravenous immunoglobulin) coadministration also shortened aCD20 drug half‐life and led to accelerated B cell recovery. Repeated aCD20 dosing restored B cell depletion and delayed allograft rejection, especially B cell–dependent, antibody‐independent allograft rejection. These data demonstrate the importance of further clinical studies of the PK/PDof monoclonal antibody treatment in inflammatory conditions. The data also highlight the disconnect between B cell depletion on peripheral blood compared to secondary lymphoid organs, the deleterious effect of IVIGwhen given with aCD20 and the relevance of redosing of aCD20 for effective B cell depletion in alloimmunity. Antigen‐independent inflammation decreases the efficacy of B cell depletion by altering the pharmacokinetics and pharmacodynamics of anti‐CD20–mediated antibody therapy, but repeated dosing restores B cell depletion to promote graft survival.