Objective: Sublingual immunotherapy (SLIT) has emerged as a potentially safe and convenient option for allergen immunotherapy for patients with inhalant allergy. Larger studies on the overall side effects and severe reactions anaphylaxis are still lacking. Study Design: Systematic review and meta-analysis. Setting: Author’s review was completed in the University of Texas Medical Branch. Methods: A systematic review and meta-analysis of prospective clinical trials focusing on SLIT safety published from January 1, 2001, to December 31, 2021, was conducted. Results: Twenty-six studies were included with analysis of 7827 patients, representing over 2.7 million SLIT doses. All studies focused on single-antigen immunotherapy. The mean duration of treatment was 11.54 months. Local side effects were present in 40.83% of patients [95% confidence interval (CI) 24.78-57.96]. Systemic side effects were encountered in 1.09% of SLIT patients (95% CI 0.57-1.78). Anaphylaxis was reported in 0.13% of patients (95% CI 0.06-0.22). Discontinuation rates due to side effects were low, at 4.32% of patients (95% CI 3.28-5.49). Conclusion: This meta-analysis shows that single-antigen SLIT is well-tolerated, with overall low rates of systemic side effects including anaphylaxis. Although there is a high rate of minor local side effect, the treatment attrition during the first year is low. With growing allergy burden worldwide, SLIT is a convenient and economically feasible option for immunotherapy. Further work is needed to evaluate long-term safety and efficacy of single as well as multi-antigen SLIT, including quality of life assessments.