For a study, the researchers wanted to find out whether premedication with desloratadine and ranitidine during oral peanut immunotherapy (OIT)/desensitization leads to fewer side effects. Approximately 43 patients with peanut allergy (mean [standard deviation (SD)] Age 7.6 [2.1] years, 37% female, 63% male, initial trigger dose [ED] 33  mg) were randomized to OIT with or without concomitant H1 and H2 antihistamine blockade or double placebo. Blinding was used for patients, research staff/investigators, and statisticians. The frequency and severity of OIT-induced adverse events were the main endpoints. The secondary objectives were quality of life and elicitation of doses for a blinded food challenge. Adverse events occurred more frequently 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 receiving antihistamines with OIT had the same risk of adverse events as patients not receiving antihistamines with OIT (HR 1.23 [95% CI 0.49-1.97]). Compared to double placebo, OIT with and without antihistamines increased the adverse event rate (4.8 and 6.4 events per patient versus 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-to-severe adverse events in OIT-treated groups (1.9 per patient vs. 4.2 per patient, IRR 0.46 [95% CI 0.24-0.89]), mainly urticaria (0.6 versus 2.1 per patient) and abdominal symptoms (0.6 versus 2.1 per patient) (2.6 versus 4.2 per patient). After treatment, all groups had identical triggering doses. Treatment with peanut OIT or placebo OIT similarly increased quality of life. Although peanut OIT with antihistamines reduced the skin and GI components of the high rate of adverse events during OIT, there were no apparent differences in QoL improvement between those treated with OIT, OIT with antihistamines, or placebo OIT . Future large randomized trials were needed to confirm that safer food allergy treatment options improve quality of life.