INTRODUCTION: Cancer-related fatigue (CRF) has been suggested to be associated with the occurrence of chemotherapy-induced nausea and vomiting (CINV). This study aims to evaluate the potential of CRF in predicting the occurrence of CINV. METHOD: This is a prospective, observational study. Recruited patients received moderately to highly emetogenic single-day chemotherapy regimens. On the day of chemotherapy, patients were instructed to provide a score (Likert scale of 0-10) to describe how CRF interfered with his or her ability to engage in daily activities and a score for how severe it was. Patients were then given a standardized 5-day diary to document their CINV events. RESULTS: A total of 473 eligible patients (median age: 55 years, interquartile range (IQR): 48-61 years) were recruited, with most of the patients diagnosed with gastrointestinal (45%) and breast (37%) cancers. The median score of fatigue interference was 3 (IQR: 0-5). After confounders were adjusted for, patients with low fatigue interference scores (≤3) were more likely to achieve complete protection (no nausea, no vomiting, and no breakthrough antiemetics) of CINV (adjusted odds ratio = 1.57, 95%CI [1.05, 2.35], p = 0.027). CONCLUSION: This is the largest study to date to evaluate the association between CRF and CINV. Patients experiencing CRF possessed a higher risk of poor control for CINV.