Onivyde, a liposome-encapsulated irinotecan, is used for advanced pancreatic, while TAS-102 (trifluridine/tipiracil) is indicated for metastatic colorectal and gastric cancers. This study aims to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profiles of liposomal irinotecan combined with TAS-102. This multicenter, phase I study utilized a 3 + 3 dose-escalation design. Patients with treatment-refractory solid malignancies received free base liposomal irinotecan at 50-70 mg/m on Day 1 and TAS-102 at 25-35 mg/m twice daily on Days 1-5 of a 14-day cycle. Patients homozygous for UGT1A128 (TA7/TA7), UGT1A16 (A/A), or double heterozygous (TA6/TA7 and G/A) alleles were excluded. Prophylactic G-CSF was allowed. Twenty-six evaluable patients were enrolled across seven dose levels of liposomal irinotecan (free-base)/TAS-102 combination: 3 patients each at level 1 (50/25 mg/m), level 2A (60/25 mg/m), level 2B (50/30 mg/m), and level 3 (60/30 mg/m); 6 at level 4A (70/30 mg/m); 3 at level 4B (60/35 mg/m); and 5 at level 5 (70/35 mg/m). An additional 15 patients were enrolled in the expansion cohort at the MTD of 70/30 mg/m (level 4A), designated as the RP2D. Overall grade 3-4 treatment-related adverse events occurred in 44.2% of 43 all treated patients, with neutropenia (16.3%), diarrhea (14%), and fatigue (11.6%). Partial responses were observed in 18.4% of patients, predominantly in neuroendocrine tumor, gastric and esophageal carcinomas. The combination of liposomal irinotecan and TAS-102 at the RP2D of 70/30 mg/m demonstrated acceptable safety and promising efficacy in refractory solid tumors, warranting further investigation.