BACKGROUND: Monogenic (or single gene) disorders are caused by 1 or more pathogenic variants in a single gene. Monogenic disorders are inherited and can result in substantial morbidity, disability, and mortality. Preimplantation genetic testing for monogenic disorders (PGT-M) can be used to screen embryos that are created via in vitro fertilization (IVF) for pathogenic variants of interest. We conducted a health technology assessment of IVF with PGT-M among people at risk of transmitting single gene disorders with an evaluation of clinical effectiveness. A report describing a rapid review of the qualitative literature, direct patient engagement, a review of published literature examining ethical considerations relating to PGT, and a rapid review of the obstetrical and neonatal harms of PGT using trophectoderm biopsy has been published separately. METHODS: We performed a systematic literature search of the clinical evidence. We conducted an overview of reviews to describe the body of systematic review evidence. We assessed the quality of each included systematic review using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). RESULTS: We included 4 systematic reviews in the clinical evidence review: 2 were of low quality and 2 were of critically low quality. We did not identify any data evaluating PGT-M with relevant comparators, such as conception (natural or via IVF) with prenatal diagnostic testing. The evidence is very uncertain about the effect of PGT-M on live births, clinical pregnancy, ongoing pregnancy, and pregnancy loss. The reported frequency of false-negative test results appears low, but the evidence is very uncertain. The impact on parental psychological outcomes is unknown. There was no evidence identified on number of IVF cycles to achieve an unaffected embryo or live birth, or parental quality of life. CONCLUSIONS: Owing to the current body of noncomparative evidence, the clinical effectiveness of PGT-M is inconclusive.