Prolonged exposure of quiescent Swiss 3T3 cells to vasopressin prevents mitogenic stimulation on subsequent addition of bombesin. This heterologous desensitization is selective and can be mimicked by vasopressin agonists, including [Lys8]vasopressin and oxytocin but not by the V1-type-specific vasopressin receptor antagonist [Pmp1,O-Me-Tyr2,Arg8]vasopressin [where Pmp is 1-(beta-mercapto-beta,beta-cyclopenthamethylene propionic acid)]. Furthermore, vasopressin-induced loss of responsiveness to bombesin can be blocked by addition of this antagonist, indicating that heterologous desensitization is mediated through the vasopressin receptor. Desensitization requires prolonged incubation (half-maximal desensitization occurring after approximately 20 hr of pretreatment) and continuous protein synthesis. Bombesin responsiveness is restored by incubation in the absence of vasopressin. Pretreatment does not alter the number, affinity, or internalization capacity of the bombesin receptors. However, the induction of the protooncogene c-fos by bombesin is profoundly inhibited after vasopressin pretreatment. We suggest that the coupling of the activated bombesin receptor to the generation of its early signals is impaired in desensitized cells.