OBJECTIVES: To study the incremental cost-effectiveness of two 5HT3 receptor antagonists -granisetron (GR) against ondansetron (ON)- in prevention treatment of Chemotherapy induced nausea and vomiting (CINV). METHODS: Prospective, multi-center, observational study on 325 naïve patients recruited at 8 Spanish Oncology Services. Consecutive patients undergoing 1st cycle with moderate to highly emetogenic chemotherapy, and scheduled antiemetic treatment based on GR or ON were enrolled. After chemotherapy (day 0), daily maximum nausea intensity and number of vomiting episodes were self-recorded during 5 more days in a diary card. Acute CINV was defined as developed in day 0, and delayed CINV as developed or persisting in days 1-5. Antiemetic “full” response was defined as: no emesis and no/mild nausea. Differences between GR and ON in adverse event costs, emergency visits, or other concomitant treatments were negligible. Only antiemetic drug direct costs were considered. Incremental Cost-Effectiveness Ratio (ICER) was computed for 1,000 and 10,000 bootstrap samples. Mean ICER values, bootstrap percentiles and cost-effectiveness scatterplots were used for comparison. RESULTS: No differences were found in acute treatment effectiveness (GR=78.7%, ON=79%) making impossible to interpret ICER values. Direct mean cost was somewhat higher for GR=36.9€ (SD=35.3) than for ON=34.1€ (SD=34.2). Delayed effectiveness was higher in GR (51.8%) than in ON (42.7%) arm, with lower mean (90%IC) costs in GR=19.54€ (16.57, 22.6) than in ON=55.26€ (46.4, 64.2) group. Bootstrap ICER mean value was 353.1 (P10= 1120.8, P90= 85.7). Scatterplots in the cost-effectiveness space showed clear segregation. Overall treatment results were similar to delayed treatment ones. CONCLUSION: No statistic differences were found between treatments in acute effectiveness, and hence cost minimization analysis was only considered. GR showed to be more cost-effective than ON in delayed and overall emesis treatment.