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Background Infusion-related reactions (IRRs) are common challenges in immuno-oncology treatments, which arise primarily from the release of histamine and other inflammatory mediators. Antihistamines play a pivotal role due to their ability to mitigate allergic reactions by blocking histamine receptors. Cetirizine, a second-generation antihistamine, may offer advantages over the traditional first-generation diphenhydramine due to its lower sedative profile. This meta-analysis compares the efficacy and safety of these two premeditations.Methods Four studies involving a total of 299 participants aged 45–70 years were analyzed ( table 1). Participants received either cetirizine or diphenhydramine as premedication prior to chemotherapy. Outcomes included IRR incidence, sedation levels, and adverse events. Subgroup analyses were conducted by infusion cycles and age groupsResults Cetirizine and diphenhydramine showed comparable efficacy in reducing IRRs (OR = 0.71, 95% CI 0.32–1.57, p > 0.40) ( table 1). Subgroup analyses indicated no significant differences by infusion cycles or age (1st dose: OR = 0.77, CI = 0.40–1.47, p > 0.43; 2nd dose: OR = 0.66, CI = 0.22–1.96, p > 0.45; 3rd dose: OR = 0.56, CI = 0.13–2.35, p > 0.43; Patients >60 years: OR = 0.63, CI = 0.26–1.57, p > 0.32; Patients <60 years: OR = 1.07, CI = 0.22–5.17, p > 0.93) (table 1). However, cetirizine demonstrated significantly lower sedation levels (SMD = -0.58, 95% CI -1.14 to -0.03, p = 0.04), with only 4% of cetirizine users reporting significant sedation compared to 58% of diphenhydramine users (p < 0.01) (table 1). Adverse events were minimal and similar between groups (OR = 0.94, 95% CI 0.56–1.56, p > 0.80) (table 1).Conclusions Cetirizine is a safer alternative to diphenhydramine for preventing IRRs, particularly in patients requiring frequent treatment cycles. These findings support integrating cetirizine into oncology premedication protocols to minimize sedation-related complications, particularly in elderly patients. Future large-scale, randomized trials are needed to confirm these results.Abstract 1066 Table 1