Background: The purpose of this Phase I trial was to evaluate the safety and toxicity of repeated normothermic intraperitoneal paclitaxel for patients with gastric cancer metastatic to the peritoneum. Methods: In patients with gastric adenocarcinoma and peritoneal carcinomatosis or positive peritoneal cytology, a Bayesian optimal interval design was used to prospectively identify the safety and tolerability of escalating doses of intraperitoneal paclitaxel administered as 3 weekly treatments followed by a 1-week break and then 3 additional weekly treatments. The primary objective was to define the maximum tolerated dose (MTD). Secondary objectives included determining the safety and tolerability of escalating doses of intraperitoneal paclitaxel and making a preliminary assessment of the anti-tumor activity based on the peritoneal carcinomatosis index (PCI) and overall survival (OS). Results: A total of 25 patients were treated between January 2020 and April 2023. The MTD for intraperitoneal paclitaxel was 100 mg/m². Five patients (20%) had dose-limiting toxic effects at 100 mg/m². Treatment-related grade 3-4 toxic effects included leukopenia in 8 patients (32%) and neutropenia in 8 (32%). Seven patients (28%) required a schedule change to every-other-week treatment. The PCI after intraperitoneal paclitaxel demonstrated progression in 5 patients (20%), stable disease in 5 (20%), and improvement in 10 (40%); 5 patients (20%) were not evaluable for PCI. Eight patients (32%) had resolution of their peritoneal disease, and 7 (28%) underwent attempted resection. The median OS from the time of diagnosis of metastatic disease was 17.9 months (95% CI 14.5-29.5) and from the date of treatment initiation was 10.3 months (95% CI 6.5-18.8). One-, 2-, and 3-year OS rates from the time of diagnosis of metastatic disease were 84%, 36%, and 22%, respectively. Pharmacokinetic analysis showed there was systemic absorption of paclitaxel and plasma AUC_0-∞ and C_max was (13955 ± 6683 h.ng/ml) and (390 ± 191 ng/ml) respectively, while intraperitoneal concentration at the end of infusion was 232 ± 65 µg/ml. Conclusions: Paclitaxel may be safely administered at an intraperitoneal dose of 100 mg/m². Neutropenia was common with weekly treatments, and we would recommend every-other-week treatment for future studies. Rates of resolution of peritoneal disease with multimodality therapy were promising, supporting future trials of this strategy and molecular profiling to identify factors associated with treatment response. Clinical trial information: NCT04220827.