For a study, researchers sought to see if desloratadine and ranitidine premedication leads to fewer side effects during peanut oral immunotherapy (OIT)/desensitization. About 43 peanut allergy patients (mean [standard deviation (SD)] age 7.6 [2.1] years, 37% female, 63% male, baseline eliciting dose [ED] 33  mg) were randomized to OIT with or without concurrent H1 and H2 antihistamine blocking, or double-placebo. Blinding was used for patients, research staff/investigators, and statisticians. The incidence and severity of OIT-induced adverse events were the essential outcomes. The secondary goals were quality of life and evoking dosages to a blinded food challenge. Adverse events were more common in the OIT groups than in the double-placebo group (hazard ratio [HR] 3.75 [95% CI 2.79-4.72]; OIT with placebo antihistamines versus double-placebo HR 4.62 [95% CI 3.61-5.62]). Patients who received antihistamines with OIT had the same risk of adverse events as those who did not get antihistamines with OIT (HR 1.23 [95% CI 0.49-1.97]). When compared to the double-placebo, OIT with and without antihistamines increased the rate of adverse events (4.8 and 6.4 events per patient against 3.5 events per patient, incidence rate ratio (IRR) 2.49 [95% CI 1.36-4.56] and 2.04 [95% CI 1.01-4.15], respectively). Pretreatment with antihistamines reduced the prevalence of moderate-severe adverse events in OIT-treated groups (1.9 per patient against 4.2 per patient, IRR 0.46 [95% CI 0.24-0.89]), primarily urticaria (0.6 versus 2.1 per patient) and abdominal discomfort (0.6 versus 2.1 per patient) (2.6 versus 4.2 per patient). After treatment, all groups had identical eliciting dosages. Treatment with peanut OIT or placebo OIT similarly increased quality of life. Even though peanut OIT with antihistamines reduced the skin and GI components of the high rate of adverse responses during OIT, there were no apparent differences in QoL improvement between those treated with OIT, OIT with antihistamines, or placebo OIT. Future comprehensive randomized trials were needed to verify that safer food allergy treatment options improve QoL.