Post-orgasmic illness syndrome (POIS) is a rare, underrecognized condition characterized by clusters of flu-like, neurologic, and allergic symptoms occurring within minutes to hours after ejaculation and lasting days. This chapter synthesizes current evidence on definition, epidemiology, proposed mechanisms, diagnosis, and management. The leading hypothesis is an immunologic reaction to autologous semen (type I/IV hypersensitivity), supported by positive skin testing and responses to hyposensitization and intralymphatic immunotherapy, although conflicting reports and non-IgE findings exist. Alternative mechanisms include neuroendocrine dysregulation, opioid-withdrawal–like states, hypogonadism, and culturally mediated syndromes. Diagnostic evaluation remains clinical, guided by Waldinger’s criteria, with multifactorial workup to exclude mimics. Treatment is individualized and symptom-directed: antihistamines or omalizumab, anti-inflammatories, alpha-1 antagonists to induce anejaculation, psychotropics, hormonal therapy, and, rarely, surgical interruption of seminal pathways. Data remain limited to small series and case reports; standardized criteria and prospective multicenter studies are urgently needed to define phenotypes and optimize therapy and long-term outcomes.