Cyclophosphamide and phosphoramide mustard produce significant vomiting. Cyclophosphamide is metabolized to phosphoramide mustard, which may ultimately contribute to vomiting after cyclophosphamide administration. The role of the chemoreceptor trigger zone (CTZ) in vomiting caused by these agents is unknown. We studied the emetic syndromes produced by iv and intracerebroventricular cyclophosphamide and phosphoramide mustard in unanesthetized normal and CTZ-ablated cats. Iv cyclophosphamide produced vomiting unpredictably, with a mean latency of 54 +/- 9 mins (mean +/- SE) in cats that vomited. A dose-response relationship was found for phosphoramide mustard-induced emesis. A dose of 200 mg/kg was consistently effective, with a mean latency of 127 +/- 6 mins. Neither agent produced predictable emesis by the intracerebroventricular route of administration. One of four CTZ-ablated cats vomited after 300 mg/kg of cyclophosphamide. Since cyclophosphamide was an unpredictable emetic stimulus, it was not possible to further evaluate the effect of CTZ ablation on cyclophosphamide-induced vomiting. However, CTZ-ablated cats given 200 mg/kg of phosphoramide mustard vomited significantly less frequently (P = 0.05 by chi-square test) and with a longer latency than nonablated animals. A temporary, severe neurotoxic reaction was observed in cats receiving greater than or equal to 3400 mg/kg of cyclophosphamide, which may have had an inhibitory effect on emesis. Phosphoramide mustard was found to be a potent emetic stimulus in cats and may contribute to the emetic response following cyclophosphamide administration. Analysis of latency data suggests that in the cat other cyclophosphamide metabolites may also contribute to the emetic syndrome.