Development of resistance to colchicine in the mouse macrophage-like cell line J774.2 coincides with the expression of a variety of phenotypic traits. A cloned subline (J7/CLC-20), maintained in 20 microM colchicine, exhibits reduced steady-state association with drug, increased presence of a 140,000-145,000 dalton (140-145 kD) phosphoglycoprotein associated with the plasma membrane, double minute chromosomes and cross-resistance to other drugs. While similar phenotypic traits are observed in J774.2 cells resistant to taxol and vinblastine, differences in the electrophoretic mobilities of the resistance-specific glycoproteins in each of the three sublines suggest that multi-drug resistant sublines exhibit specificity for individual drugs. In an attempt to elucidate the relationships between the phenotypic traits associated with colchicine resistance, the degree of colchicine resistance in J7/CLC-20 cells was modulated and the levels of expression of the phenotypic traits were quantitated. In the absence of colchicine in the growth medium, J7/CLC-20 cells reverted to drug sensitivity within 35 days. A decrease in the level of resistance coincided with coordinate changes in both the quantity of the resistance-specific glycoprotein and the average number of double minute chromosomes. We propose that the emergence and disappearance of the resistance-specific glycoprotein and double minute chromosomes may be closely linked. However, J7/CLC-20 cells which had regained their drug sensitivity after growth in drug-free medium maintained a reduced level of steady-state drug association. The persistence of reduced drug association in cells that have reverted to a drug-sensitive state suggests that this phenomenon, although related to colchicine resistance, need not be the primary or only mechanism of drug resistance.