Background: The SQ tree SLIT-tablet has recently been approved for treatment of tree pollen allergy. Health care workers should be provided with detailed safety data for clinical use. Objective: To assess the tolerability and safety of the SQ tree SLIT-tablet in adults and adolescents. Methods: Safety data were pooled from two phase-II and one phase-III double-blinded, randomized, placebo-controlled trials including adults and adolescents with allergic rhinitis and/or conjunctivitis treated before and during one pollen season once-daily with the SQ tree SLIT-tablet (12 SQ-Bet) or placebo. Results: The most frequently reported IMP-related AEs with 12 SQ-Bet were oral pruritis (39% of subjects) and throat irritation (29%). IMP-related AEs were mainly mild or moderate in severity, and the majority resolved without treatment and did not lead to treatment interruption/discontinuation. With 12 SQ-Bet, oral pruritus was more frequent among PFS subjects (45%) than in subjects without PFS (29%). A greater proportion of PFS subjects interrupted treatment (19%) than subjects without PFS (7%). The 12 SQ-Bet did not seem to induce an increased risk of asthma: 7 events were reported in 7 subjects with 12 SQ-Bet and 11 in 10 subjects with placebo. No differences were seen in the risk of moderate to severe IMP-related AEs regardless of age, PFS status and asthma medical history. Conclusions: The 12 SQ tree SLIT-tablet was well tolerated in tree pollen allergic subjects with no major safety concerns detected. This safety profile supports daily at-home sublingual administration once the first dose is tolerated when administered under medical supervision.