Abstract
Post-Orgasmic Illness Syndrome (POIS) is a rare condition characterized by flu-like symptoms after ejaculation, lasting several days and impairing quality of life. A 62-year-old man developed POIS after percutaneous epididymal sperm aspiration, with symptoms lasting seven days and worsening over six years. Multiple treatments offered minimal relief until combined therapy with tamsulosin, ebastine, escitalopram, and montelukast achieved complete resolution and restored sexual function. Immune hypersensitivity to seminal or epididymal antigens is a leading hypothesis. The success of α-blockers, antihistamines, and SSRIs highlights the interplay between immune, autonomic, and psychological mechanisms. POIS is a complex, underrecognized disorder. Multimodal therapy addressing both immune and neuropsychological pathways may yield optimal outcomes. Greater awareness and standardized diagnostic and treatment criteria are needed to improve management and research.