Post-orgasmic Illness Syndrome (POIS) is an uncommon condition characterized by the emergence of flu-like and allergy-like symptoms following ejaculation, lasting for a period of 2 to 7 days. The syndrome presents in two primary age-related onset patterns: one during puberty and another initiating later in adult life. Although the condition leads to significant emotional distress and a decline in quality of life, its true prevalence remains elusive due to underreporting and underdiagnosis. The leading etiological hypothesis suggests an immunological mechanism, specifically an allergic reaction to the patient's own sperm. A handful of studies support this hypothesis, providing compelling evidence that hyposensitization treatment using autologous sperm effectively alleviates the symptoms of POIS. This suggests that an immune response against sperm components may be the primary underlying cause. However, a definitive understanding of the syndrome's pathophysiology requires further investigation.