Resistance to glucocorticoids (GCs) frequently appears during treatment of hematological malignancies. This study investigates the phenotypical alterations observed in human myeloma cell sublines resistant to glucocorticoids. Using the RPMI8226 cell line, the cytotoxic efficiencies of four glucocorticoids, and the phenotypes of isolated resistant sublines were analyzed. Methyl-prednisolone and dexamethasone exhibited the higher toxic effects on RPMI8226 cells. All corticoids were able to induce drug-resistance. Resistant sublines showed an increased expression of the alpha-isoform of the glucocorticoid receptors (GRs), and specific modulations in CD23, CD38, CD44 and CD58 expressions. Thus, glucocorticoid resistance in RPMI8226 cells is accompanied by significant phenotypical alterations that could be implicated in survival enhancement to therapy and/or tumor spreading.