Background: NEPA is a fixed combination antiemetic of the NK₁-receptor-antagonist (RA) netupitant and the 5-HT₃-RA palonosetron. Primary objective of this prospective non-interventional study in Germany was to assess quality of life of cancer patients (pts) undergoing moderately (MEC) or highly (HEC) emetogenic chemotherapy (CT) who received NEPA for prophylaxis of nausea and vomiting (CINV). Secondary objectives were patient reported outcomes as well as effectiveness and safety of NEPA. Here we report final data of the quality of life analysis. Methods: The study included 2.405 pts in 162 centers receiving 3 consecutive cycles of CT as one or two day MEC or HEC. Primary endpoint was impact of quality of life (QoL) due to vomiting or nausea, documented by Functional Living Index–Emesis (FLIE) questionnaires. Effectiveness was reported in patient diaries. Complete response (CR) was defined as no emesis and no rescue medication (RM). Non-significant nausea (NSN) was no or mild nausea. Adverse events (AEs) were reported on d1–21 of each cycle. Results: 2.173 patients were included in the final analysis (full analysis set; FAS). The majority of patients (n = 1976; 91%) received 1-day chemotherapy, 64% HEC, 36% MEC. Median age was 58 years and the majority (85%) was female. Cancer diagnoses: breast 66%, gastrointestinal 10%, ovarian 7% or lung 5%, other 12%. Chemotherapy: AC 57%, carboplatin 19%, cisplatin 8%, oxaliplatin 8% and other 8%. 84% of pts with HEC and 82% with MEC felt no impact on daily life due to vomiting in cycle 1 remaining constant in C2 and C3. 54% HEC patients and 59% MEC patients reported no impact on daily life due to nausea in cycle 1. CR rates ranged between 81-84% and were comparable between different HEC or MEC. NSN rates in MEC ranged from 75% (MEC) to 62% (HEC). Drug-related AEs were rare with constipation, fatigue, insomnia, and nausea as the most common (in > 1% pts). Conclusions: NEPA was highly effective in the prevention of CINV and maintenance of QoL in this real world study. Over 80% of pts reported that their daily live was not influenced by emesis while nausea was more difficult to control. Effectiveness was high and patients and physicians estimate was comparable.