Background Peanut oral immunotherapy (POIT) with or without omalizumab can improve tolerance in peanut-allergic children. Data regarding adults are limited. We evaluated the safety and efficacy of omalizumab plus POIT over 48 weeks in adults. Methods Adults allergic to ≤300mg peanut protein following double-blind, placebo-controlled peanut challenges (DBPCPCs) received omalizumab 300mg q4 weeks x 6 doses. Daily POIT commenced at Week 12 (25mg), increasing to a maximum 300mg at Week 24, followed by 300mg daily. Participants underwent DBPCPCs up to 1000mg at Weeks 24 and 48. Primary outcome (tolerance of ≥300mg peanut protein) was analysed by intention-to-treat. Changes from baseline and from Week 24 were analysed using paired t-tests. Results Of 25 patients treated (median age 24 years, mean eliciting dose 30mg, mean skin prick [SPT] diameter 10.6mm), all tolerated ≥300mg peanut protein at Week 24, and 22 (88%) at Week 48 (p=0.08; 2 withdrew due to anxiety, 1 lost to follow up), Food Allergy Quality of Life score improved (mean change -29.6 [scale 0-174], p<0.05), and SPT diameter decreased (mean 3.5mm, p<0.0001). Basophil activation by total peanut protein, Ara H2 and Ara H6 decreased significantly at Week 24 (mean -1.2% to -48.0%, all p<0.05) but not at Week 48. Of 169 allergic reactions to POIT, 61 (36.1%) were treated with antihistamine and three (1.8%) with adrenaline. Adverse event (AE) rate for a moderate-severe, POIT-related AE was 0.002/dose [Number needed to harm (NNT H)=500]. Conclusion POIT plus omalizumab for 24 weeks safely induced tolerance of 300mg peanut protein over 48 weeks in peanut-allergic adults.