The Spanish Pharmacovigilance System for Medicines for Human Use (SEFV-H) is responsible for recording and evaluating adverse reactions suspected to be due to the medicines. The aim of this study was to review all reports of suspected adverse drug reaction (ADRs) in the SEFV-H database derived from the gender-affirming hormone therapy (GAHT). For this purpose, we consulted the Andalusian Centre for Pharmacovigilance (CAFV) and used three search algorithms to select only those reports derived from hormone therapy used by trangender people. A total of 21 reports were obtained, 13 corresponding to masculinizing therapy with testosterone and 8 corresponding to feminising therapy with estradiol and cyproterone acetate. Most of these reports were of non-severe symptoms. Skin and subcutaneous tissue disorders, neoplasms, psychiatric, vascular, gastrointestinal and nervous system disorders were the most common suspected ADRs. The median age was 23.6 years for masculinising therapy and 27 years for feminising therapy. More reports are needed to represent transgender people in the GAHT, and it is important to involve health professionals and the general population in pharmacovigilance efforts. Plain Language Summary In Spain, the body responsible for the evaluation of adverse reactions due to medication, or adverse drug reactions (ADRs), is the Spanish Pharmacovigilance System for medicinal products for Human Use (SEFV-H). The aim of this study was to analyse suspected ADRs associated with gender-affirming hormone therapy, a treatment used by transgender people to align their physical characteristics with their gender identity. In order to do this, a search was carried out in the SEFV-H database. A total of 21 reports of ADRs due to sex-affirming hormone therapy were identified. Of these, 13 involved masculinizing therapies with testosterone and 8 feminizing therapies with oestradiol and cyproterone. Most of the adverse reactions reported were not serious, with the most frequent being skin disorders, neoplasms, psychiatric, vascular, and gastrointestinal disorders. The median age of the affected individuals was 23.6 years for those receiving masculinizing therapy and 27 years for those on feminizing therapy. The limited number of reports available in the SEFV-H database limits the ability to draw definitive conclusions about ADRs associated with this type of treatment. Therefore, it is essential to encourage the involvement of healthcare professionals in pharmacovigilance activities to better assess the safety of medications used in gender-affirming hormone therapy.