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Introduction: Post-Orgasmic Illness Syndrome (POIS) is a rare, debilitating condition characterized by a constellation of systemic, allergic, cognitive, and emotional symptoms occurring shortly after orgasm. These symptoms severely impact sexual functioning and quality of life. Despite its profound effects, POIS remains poorly understood, underrecognized, and without a definitive treatment.Case Presentation: We report two cases observed in a specialized sexology consultation. The first case concerns a 49-year-old married man presenting with secondary-onset POIS. His symptoms, including muscle rigidity, genital burning, and profound fatigue, consistently emerged after ejaculation, whether during intercourse or masturbation. Extensive investigations revealed no abnormalities. Management included pharmacotherapy (fluvoxamine 50 mg daily and cyclobenzaprine 10 mg daily), psychological support, and sexual counseling. The patient adapted sexual practices, including adopting a lateral coital position to minimize exposure to seminal fluid. Although symptoms persisted after each orgasm, these interventions led to an overall improvement in quality of life.The second case involves an 18-year-old male experiencing primary-onset POIS since puberty. He developed severe fatigue, cognitive dysfunction, low-grade fever sensations, irritability, and abdominal discomfort following ejaculation. Comprehensive evaluations excluded infectious and allergic causes. Notably, the patient required psychiatric hospitalization after a severe behavioral disturbance characterized by agitation and hetero-aggressiveness post-orgasm. Treatment involved antipsychotic and antidepressant therapy, psychological support and psychoeducation.Conclusion: These cases highlight the heterogeneous and distressing nature of POIS and its profound impact on sexual health and psychosocial functioning. Multidisciplinary management combining pharmacological, psychological, and sexual interventions may yield partial symptom control and improve patients' quality of life. Increased clinician awareness and further research are urgently needed to advance understanding, diagnosis, and therapeutic strategies for POIS.