PURPOSE: This study aimed to provide the first comprehensive analysis of the health status of transgender and gender-diverse (TGD) adults in Italy, addressing disparities in physical and mental health and access to gender-affirming care. By combining self-reported health data with clinical evaluations and incorporating demographic and clinical variables, the research offers a robust and previously unavailable health profile of this population. METHODS: An anonymous online survey targeting TGD adults across Italy was conducted from June 2020 to June 2021. The survey consisted of self-reported health assessments and clinician-conducted evaluations, collecting data on chronic physical conditions, mental health disorders, infectious diseases, and gender-affirming care. Statistical analyses, including chi-square tests and logistic regression, identified associations between demographics and health outcomes. RESULTS: Among 959 participants, mental health disorders were prevalent, with over half experiencing depression and/or anxiety. Non-binary individuals reported poorer health compared to binary individuals. Chronic conditions such as thyroid disorders were more common in individuals assigned female at birth (AFAB), whereas those assigned male at birth (AMAB) had higher rates of osteoporosis and sexually transmitted infections. Key health predictors included age, education, employment, and engagement in gender-affirming hormone therapy. CONCLUSION: The study reveals stark health disparities among TGD individuals in Italy, emphasizing the need for targeted health policies, expanded mental health services, and specialized healthcare provider training.