The aim of the present study was to evaluate the presence of psychiatric diseases/symptoms in transsexual patients and to compare psychiatric distress related to the hormonal intervention in a one year follow-up assessment. We investigated 118 patients before starting the hormonal therapy and after about 12 months. We used the SCID-I to determine major mental disorders and functional impairment. We used the Zung Self-Rating Anxiety Scale (SAS) and the Zung Self-Rating Depression Scale (SDS) for evaluating self-reported anxiety and depression. We used the Symptom Checklist 90-R (SCL-90-R) for assessing self-reported global psychological symptoms. Seventeen patients (14%) had a DSM-IV-TR axis I psychiatric comorbidity. At enrollment the mean SAS score was above the normal range. The mean SDS and SCL-90-R scores were on the normal range except for SCL-90-R anxiety subscale. When treated, patients reported lower SAS, SDS and SCL-90-R scores, with statistically significant differences. Psychiatric distress and functional impairment were present in a significantly higher percentage of patients before starting the hormonal treatment than after 12 months (50% vs. 17% for anxiety; 42% vs. 23% for depression; 24% vs. 11% for psychological symptoms; 23% vs. 10% for functional impairment). The results revealed that the majority of transsexual patients have no psychiatric comorbidity, suggesting that transsexualism is not necessarily associated with severe comorbid psychiatric findings. The condition, however, seemed to be associated with subthreshold anxiety/depression, psychological symptoms and functional impairment. Moreover, treated patients reported less psychiatric distress. Therefore, hormonal treatment seemed to have a positive effect on transsexual patients’ mental health.