Background <p>Nano-liposomal irinotecan plus 5-fluorouracil and leucovorin (Nal-IRI/FL) is an established second-line chemotherapy for advanced pancreatic cancer (APC). Standard antiemetic prophylaxis for this moderately emetogenic regimen includes a 5-hydroxytryptamine (5-HT₃) receptor antagonist and dexamethasone (Dex). However, steroid use may worsen glucose intolerance in patients with diabetes mellitus (DM), and evidence supporting Dex-omitting strategies remains limited.</p> Methods <p>We retrospectively compared prophylactic antiemetic efficacy between Dex-omitting (no steroid use) and Dex-sparing (day 1 only) regimens combined with a 5-HT₃ receptor antagonist and neurokinin-1 (NK1) receptor antagonist in patients with APC who received Nal-IRI/FL between October 2020 and August 2024. The primary outcome was total control (TC), defined as no nausea, vomiting, or rescue medication use within 120&#xa0;h.</p> Results <p>Patients were categorized into Dex-sparing (<i>n</i> = 61) and Dex-omitting (<i>n</i> = 13) groups. Baseline characteristics were similar except for a higher prevalence of DM in the Dex-omitting group (31% vs. 100%, <i>P</i> &lt; 0.01). TC rates were comparable (80% vs. 69%, <i>P</i> = 0.46). Relative dose intensity was slightly higher in the Dex-omitting group (Nal-IRI, 55% vs. 62%; 5-FU, 59% vs. 68%). Progression-free survival (5.2 vs. 5.0&#xa0;months, <i>P</i> = 0.84) and overall survival (10.1 vs. 9.4&#xa0;months, <i>P</i> = 0.56) were also similar.</p> Conclusions <p>Steroid-omitting antiemetic therapy in combination with a 5-HT₃ receptor antagonist and NK₁ receptor antagonist appears to be a feasible option for patients with APC receiving Nal-IRI/FL, particularly those with diabetes mellitus. However, larger prospective studies are needed to validate these findings.</p>