Human seminal plasma (HSP) hypersensitivity is defined as a spectrum of systemic and/or localized symptoms after exposure to specific protein components in seminal plasma. The major antigen is believed to be prostate-specific antigen, but other proteins are likely involved in this heterogenous disorder. There are no known risk factors for developing seminal plasma hypersensitivity, although women who develop systemic symptoms are more frequently atopic. Of interest, for both systemic and localized forms, symptoms can manifest after first time intercourse in up to 50% of cases. Diagnosis requires a careful history. The gold standard for diagnosing HSP is that symptoms are completely abated with the use of a condom prophylactic. Although women with HSP hypersensitivity often have difficulty conceiving due to their inability to have unprotected sexual intercourse, infertility has not been demonstrated to be related to HSP hypersensitivity. Patients with HSP hypersensitivity often elicit positive skin prick testing and/or serum-specific immunoglobulin E to whole seminal fluid or fractionated seminal plasma proteins. Treatment involves either avoidance with the use of condoms, an intravaginal graded challenge using dilutions of whole seminal fluid, or subcutaneous desensitization to relevant fractionated seminal plasma proteins obtained from the woman's sexual partner. In most cases, treatment using ≥ 1 of the above approaches has been very successful.