Because dexamethasone is often included as an antiemetic in chemotherapy protocols that involve cisplatin and because cisplatin has been shown to increase the in vitro lysis of tumor cells by natural cytotoxic (NC) effector cells, we determined the NC activity of 27 patients who received dexamethasone in conjunction with seven different cisplatin-based chemotherapy protocols. The results of this analysis showed that the NC activity of patients who received cisplatin-based chemotherapy protocols that included dexamethasone was reduced significantly 24 hours after treatment compared with before treatment (P less than 0.001). The addition of dexamethasone (at a concentration equivalent to the plasma level of patients treated with dexamethasone) to the in vitro assay of NC activity caused a significant decrease in NC activity compared with when dexamethasone was not added (P less than 0.001). There was no cumulative effect of dexamethasone in that the reduction of NC activity by dexamethasone was not significantly different in patients who had been treated previously at least four times and in patients who were treated for the first time. When dexamethasone was not included in the chemotherapy protocol the NC activity of 19 patients was not reduced 24 hours after treatment. These results indicate that dexamethasone causes a significant reduction in NC activity. Although the tumor surveillance role of human NC cells in vivo has not been established, the effect of dexamethasone on NC cells suggests that additional research of the effect of dexamethasone in cisplatin-based chemotherapy protocols is warranted.