BACKGROUND Post-orgasmic illness syndrome (POIS) is a rare disease with an unknown etiology and pathophysiology. Several publications have previously reported successful results with various treatments, including antihistamines, selective serotonin reuptake inhibitors, and non-steroidal anti-inflammatory drugs. Here, we report the successful treatment of POIS with omalizumab in a patient with negative skin tests for self-semen with complete resolution of symptoms. So far, there has been only 1 previous report of omalizumab treatment for this syndrome. CASE REPORT A 22-year-old man with constitutional, neurological, gastrointestinal, and allergic-like symptoms after ejaculation presented to our clinic. The patient had a negative intradermal test for self-semen, normal tryptase levels (pre- and post-ejaculation), and elevated total IgE. Several treatments had been prescribed. The most efficient combination treatment prior to omalizumab included high-dose antihistamines plus anti-inflammatory medications (steroidal or non-steroidal). This regimen alleviated some but not all his symptoms. Due to the nature of the symptoms, we hypothesized that IgE and mast cells could be involved in the pathophysiology of POIS in this patient. He was started on omalizumab, with complete resolution of symptoms. After 7 months, a treatment cessation attempt resulted in recurrence of the symptoms. Currently, while on omalizumab, the patient is symptom-free and feels comfortable engaging in sexual activity. CONCLUSIONS Omalizumab may be considered for the treatment of POIS in patients with allergy-like symptoms and symptoms that cannot be controlled with other medications, even in the absence of a positive skin test to semen. Lower doses may be ineffective.