Purpose: Controversy exists as to if, and when, gender affirmative (GA) treatment should be offered to individuals with gender dysphoria (GD) and co-existing psychosis. Concerns exist regarding a high risk of misdiagnosis, regret afterward due to impulsive decision making, and deterioration of psychotic symptoms. This case series aims at extending the sparse literature on GA treatment in this population by identifying challenges in diagnosis and treatment and offering recommendations to overcome them. Case Series: The authors present case descriptions of two transgender men and two transgender women in the age range of 29-57 years with a diagnosis of GD and a schizophrenia-related diagnosis. All had undergone GA treatment with a minimum follow-up of 3 years. The gender diagnosis was complicated by the fact that feelings of GD were only shared after the onset of psychosis, and GA treatment was hampered by the persistence of mild psychotic symptoms despite antipsychotic treatment. Close communication with the psychosis treating clinicians proved useful to address these problems. GA treatment was paralleled by a stabilization of psychotic symptoms, and adherence to and satisfaction with the therapy was high. Conclusion: These case examples show that GA treatment is possible and safe in this vulnerable population.