Ragweed sublingual immunotherapy (SLIT) tablet reduces symptoms and symptom-relieving medication use in adults with allergic rhinitis with or without conjunctivitis (AR/C) but has not been evaluated in children. This international, multicenter, double-blind, placebo-controlled trial evaluated the efficacy and safety of ragweed SLIT-tablet in children with AR/C. Children (N= 1025; 77.7% polysensitized) aged 5 to 17 years with ragweed pollen-induced AR/C with or without asthma (FEV1 ≥80% predicted) were randomized 1:1 to daily ragweed SLIT-tablet (12 Amb a 1-Unit) or placebo for up to 28 weeks (NCT02478398). The primary end point was the average total combined score (TCS; sum of rhinoconjunctivitis daily symptom score [DSS] and daily medication score [DMS]) during peak ragweed pollen season (RPS). Key secondary end points were TCS during the entire RPS, and DSS and DMS during the peak RPS. Relative TCS (95% CI) improvements with ragweed SLIT-tablet versus placebo were-38.3% (-46.0% to-29.7%; least square [LS] mean difference,-2.73; P < .001) during peak RPS and-32.4% (-40.7% to-23.3%; LS mean difference,-1.86; P < .001) during the entire RPS. DSS and DMS during peak RPS improved with SLIT-tablet versus placebo by-35.4% (-43.2% to-26.1%; LS mean difference,-1.40; P < .001) and-47.7% (-59.8% to-32.5%; LS mean difference,-1.84; P < .001), respectively. Asthma DSS, short-acting β-agonist use, and nocturnal awakenings during peak RPS improved with SLIT-tablet versus placebo by-30.7%,-68.1%, and-75.1%, respectively (all nominal P ≤ .02). No events of anaphylaxis, airway compromise, or severe treatment-related systemic allergic reactions were reported. Ragweed SLIT-tablet significantly improved symptoms and decreased symptom-relieving medication use in children with ragweed pollen-induced AR/C and was well tolerated.