The control of P-glycoprotein (Pgp) expression in multidrug-resistant cells (MDR) is complex and may be regulated at different levels. We have investigated Pgp stability in four different human and hamster MDR cell lines. Using a pulse-chase procedure we show that Pgp half-life is between 14 and 17 h in all these cell lines when they are growing exponentially. However, in the presence of a low level of serum, Pgp half-life is increased four to sixfold. A similar effect is observed when the cell cultures are maintained in high cell density. The increased Pgp stability appears to be differently regulated as serum deprivation results in a general enhanced degradation of total cytoplasmic and membrane proteins. Moreover, the observed serum effect suggests the involvement of growth factors in the control of Pgp stability. These findings suggest that protein stability may be an important factor in the regulation of Pgp expression.