P‐glycoprotein 170 encoded by the MDR‐1 gene mediates export of substrates including some immunosuppressive drugs. Rapamycin was compared to cyclosporine A for its ability to inhibit P‐glycoprotein on normal human peripheral blood mononuclear cells (PBMC). Rhodamine 123 dye efflux measures P‐glycoprotein activity and inhibition of P‐glycoprotein results in dye retention. Normal CD4+, CD8+ and B cells include a substantial subset with cyclosporine A‐sensitive rhodamine efflux. Rh123 dye efflux is also inhibited by rapamycin at comparable drug levels used in transplant models. CsA is approximately 100‐fold more effective on inhibition of PBMC P‐gp than is RAPA. P‐glycoprotein inhibition of ex vivo lymphocytes with three multi‐drug resistant T‐cell lines showed susceptibility of P‐glycoprotein to rapamycin dependent on the cell type. Compared to cyclosporine A, the reduced ability of rapamycin to inhibit P‐glycoprotein reflects a reduced avidity in its binding to P‐glycoprotein and perhaps increased access to the cell interior. The increased efficiency of RAPA as an immunosuppressive may in part be a result of its relatively low avidity for P‐glycoprotein. The authors speculate that interactions with P‐glycoprotein may partially modulate the immunosuppressive effects of rapamycin.