Objective This study determined the incidence of hypersensitivity reactions in patients receiving oxaliplatin-based chemotherapy while on H1-receptor antagonists (H1RAs). Prophylaxis for patients receiving oxaliplatin is not currently recommended. H1RAs are used for the treatment of reactions; however, prophylactic H1RAs have not been well-studied. Methods This retrospective chart review included patients with solid tumor malignancies who received H1RAs while on oxaliplatin-based chemotherapy between August 1, 2016 and October 31, 2019. Results Of fifty-one patients, there were four hypersensitivity reactions (8%), most of which were mild, occurred within 60 minutes of the start of the infusion, and did not result in an interruption in treatment. One severe reaction occurred, which required discontinuation of therapy. Forty-two patients (82%) were able to receive at least 9 cycles of oxaliplatin without a reported reaction. Conclusion In this observational study, the incidence rate of hypersensitivity reactions in patients receiving oxaliplatin while on H1RAs was lower than reported in previous literature. Most reactions were mild, and patients were able to continue oxaliplatin-based therapy. With future, randomized controlled trials, H1RAs may prove to be effective in preventing or delaying the onset of hypersensitivity reactions related to oxaliplatin.