The substance P (neurokinin‐1) receptor belongs to the family of seven putative transmembrane domain receptors that are coupled via G proteins to phospholipase C activation. Homologous desensitization of substance P‐stimulated responses has been described in various systems. The rat neurokinin‐1 receptor and a truncated mutant lacking the carboxyl‐terminal region were expressed in Chinese hamster ovary cells to examine the mechanisms of substance P‐induced desensitization. Wild‐type and truncated receptor‐bearing cells were indistinguishable in agonist binding affinity and EC50 of substance P‐induced accumulation of 3H‐inositol phosphates. Substance P‐induced responses continued for 30–45 min in cells expressing wild‐type and truncated receptors as well as in rat LRM‐55 and human U373 cells, which express endogenous neurokinin‐1 receptors. In transfected cells expressing the wild‐type receptor, CP‐96,345 added 15 min after substance P blocked further responses, demonstrating the continuing presence of responsive receptors. The rates of accumulation of 3H‐inositol phosphates were four times greater in the initial 15 s of stimulation than for the next 20 min for both wild‐type and truncated receptor types. This decrease in rate of substance P‐stimulated phosphatidylinositol hydrolysis is therefore not dependent on the carboxyl‐terminal region of the rat neurokinin‐1 receptor, which contains 26 serine and threonine residues. These results are discussed in relation to current ideas regarding neurokinin‐1 receptor desensitization.