Background: Rolapitant is a highly selective competitive long acting NK-1 receptor antagonist that successfully achieved the primary endpoint of complete response (no emesis and no rescue medication) in the delayed phase of CINV in two phase 3 studies in subjects receiving MEC or HEC. In addition, these studies evaluated the safety and tolerability of rolapitant in these subjects. Methods: Two separate phase 3 double-blind active control studies were conducted. 1369 subjects scheduled to receive MEC (cyclophosphamide, doxorubicin, epirubicin, carboplatin, ifosfamide, irinotecan, daunorubicin or cytarabine), and 555 subjects scheduled to receive HEC (≥60 mg/m² cisplatin) were randomized 1:1 to either (1) rolapitant 200 mg + granisetron + dexamethasone or (2) placebo + granisetron + dexamethasone. Adverse events (AE) and serious adverse events (SAE) were collected for all subjects. Results: AE rates in cycle 1 were similar across rolapitant and control groups for both the MEC and HEC studies (63.9% vs 66.0%; 64.7% vs 60.2%, respectively). The most frequent AEs observed across both the rolapitant and control groups, respectively, for the MEC study were fatigue (16.3% vs 15.4%), constipation (10.3% vs 14.1%) and alopecia (11.3% vs 12.3%); and for the HEC study were constipation (7.4% vs 10.9%), asthenia (6.6% vs 11.3%) and neutropenia (9.9% vs 6.9%). SAEs rates in cycle 1 were also similar across rolapitant and control groups for both the MEC and HEC studies (6.6% vs 7.1%; 12.5% vs 14.2%, respectively). The most frequent SAEs across both the rolapitant and control groups, respectively, for the MEC study were febrile neutropenia (1.2% vs 2.1%), neutropenia (0.3% vs 0.9%) and neutrophil count decrease (0.3% vs 0.6%); and for the HEC study febrile neutropenia (0.7% vs 1.1%), neutropenia (0.7% vs 1.1%) and thrombocytopenia (1.1% vs 0.7%). No serious, related and unexpected AEs were reported for either study. Conclusions: Rolapitant 200 mg in combination with a 5-HT3 receptor antagonist and dexamethasone was demonstrated to be safe and well tolerated in two global phase 3 studies in subjects receiving HEC or MEC. Clinical trial information: NCT01500226.