Purpose <p>Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with oxaliplatin- and irinotecan-based chemotherapy regimens. Because these agents are typically administered sequentially in colorectal cancer (CRC) treatment and have similar emetogenic risk, we assessed the real-world feasibility of predicting CINV during irinotecan treatment based on response to prior oxaliplatin.</p> Methods <p>Patients with metastatic CRC who subsequently received an irinotecan-fluoropyrimidine-based regimen after prior treatment with an oxaliplatin-fluoropyrimidine-based regimen were retrospectively evaluated. Patients were divided into a control group (those who achieved total control [TC] during the first cycle of the oxaliplatin-based regimen) and a CINV-experience group (those who did not achieve TC during this cycle). The primary endpoint was TC rate during the delayed phase (24–120&#xa0;h after treatment initiation) of the first irinotecan-based regimen.</p> Results <p>TC rate in the delayed phase was significantly lower in the CINV-experience group than that in the control group (31.8% and 81.8%, <i>P</i> &lt; 0.0001, n = 44 in each group), which was also confirmed in the overall phase (0–120&#xa0;h). The incidences of delayed and overall nausea and anorexia in the control and CINV-experience groups were 18.2% and 68.2% (<i>P</i> &lt; 0.0001), 18.2% and 70.5% (<i>P</i> &lt; 0.0001), and 25.6% and 61.4% (<i>P</i> = 0.001), respectively. These findings were confirmed in the propensity score–matched population and across different irinotecan or oxaliplatin dose levels.</p> Conclusions <p>Our study suggests that patients who experienced CINV during prior oxaliplatin-based treatment are at an increased risk of developing symptoms during subsequent irinotecan-based treatment.</p>