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The objective of this study was to investigate the ability of the anti-CD20 antibody, Rituximab (RTX), to inhibit the activity of P-glycoprotein (P-gp), and reverse multidrug resistance (MDR) in 2 P-gp+/CD20+ lymphoma cell lines. We determined whether RTX would chemosensitize the 2 P-gp+ cell lines in vitro, and inhibit the ability of the cells to efflux Rhodamine 123. One cell line was infected with an MDR1 vector and the other was generated by drug selection. We also determined whether RTX induced P-gp to translocate out of lipid rafts. RTX chemosensitized 2 different MDR cell lines, inhibited the activity of P-gp in both, and induced P-gp to translocate out of lipid rafts in the 1 cell line that was studied in greater detail. In contrast, 3 other anti-CD20 antibodies did not chemosensitize, inhibit the activity of P-gp, or induce it to translocate out of rafts, despite the fact that 1 antibody recognized the same epitope on CD20. Our results suggest that RTX can chemosensitize 2 CD20+/P-gp+ cell lines in vitro by inhibiting the activity of the P-gp pump. The inhibition of P-gp activity correlated with the ability of RTX to induce P-gp to translocate out of lipid rafts. Although the mechanisms by which RTX effects P-gp translocation and activity are not yet known, they are not associated with acid-sphingomyelinase activation in raft microdomains, as described for the antiproliferative activity of RTX.