Human KB carcinoma cells were selected in sequential steps for resistance to colchicine and found to be cross-resistant to multiple drugs, including vinblastine, adriamycin, and actinomycin D. Compared with the parental line, the multiply resistant cells have decreased amounts of two [35S]methionine-labeled proteins with apparent molecular masses of 75 and 72 kDa. These proteins reappear in a revertant, drug-sensitive cell line. Both proteins are labeled with [14C]glucosamine and are retained on a wheat germ agglutinin-agarose column, indicating that they are glycoproteins. These data suggest that in this human cell line, these two glycoproteins can serve as a marker of the multiple drug-resistance phenotype and may play a role in its etiology.