Background: Previous studies have only evaluated intravenous histamine H2 receptor antagonists for use as paclitaxel premedication. This study aims to investigate whether oral famotidine is non-inferior to intravenous ranitidine as a premedication to prevent paclitaxel-associated hypersensitivity reactions. It could provide guidance on the use of alternative orally administered agents.Methods: It is a retrospective, multi-center, non-inferiority, historical control cohort study. Paclitaxel-naïve adult patients who began treatment with paclitaxel between August 2018 and December 2020, and received all cycles of paclitaxel in seven tertiary public hospitals in Hong Kong were enrolled. The patients received either intravenous ranitidine (control group) or oral famotidine (study group) as the premedication on the day of paclitaxel infusion. The primary outcome was the occurrence of a paclitaxel-induced hypersensitivity reaction of any severity during any cycle. The proportion of patients with the primary outcome in each group were compared by the two-proportion Z-test. The non-inferiority margin was pre-defined as an absolute hypersensitivity reaction rate difference of 5%.Results: We enrolled 1282 paclitaxel-naïve adult patients. Patients in both control (n = 635) and study (n = 647) groups had a median age of 59 years, and 476 (75%) and 485 (75%) were females, respectively. A median of five cycles of paclitaxel were administered in both groups. Hypersensitivity reactions occurred in 121 (19%) patients in study group, and 105 (17%) patients in control group (difference: +2.2%; 95% confidence interval [CI]: -2.02% to +6.35%; non-inferiority one-sided p = 0.092). A subgroup analysis of patients receiving standard-dose steroid premedication demonstrated a hypersensitivity reaction rate difference of +0.4% (95% CI: -3.97% to +4.83%, non-inferiority one-sided p = 0.021).Conclusions: We found no statistically significant differences in the hypersensitivity reaction rates between intravenous ranitidine and oral famotidine. Oral famotidine was not found to be non-inferior to intravenous ranitidine as a paclitaxel premedication based on the pre-defined non-inferiority margin. The use of oral famotidine with standard-dose steroid as premedication may provide better protection against hypersensitivity reactions.