OBJECTIVE: Previous studies have suggested that interferon-alpha may be an effective treatment for some women with vulvar vestibulitis. We evaluated whether women with this syndrome had a deficiency in endogenous and induced interferon-alpha production. STUDY DESIGN: Blood was collected in heparinized tubes from 62 women with vulvar vestibulitis and 47 control women of similar age and ethnicity. Whole blood cultures were incubated in the presence of 0.1 ng/mL lipopolysaccharide (induced) or culture medium (uninduced) for 18 to 20 hours. Aliquots were tested for interferon-alpha levels by enzyme-linked immunosorbent assay. Vestibular samples were tested for human papillomavirus by polymerase chain reaction. Aliquots were also characterized for alleles of the polymorphic gene, interleukin-1 receptor antagonist, by polymerase chain reaction. RESULTS: In uninduced cultures, interferon-gamma was present in 68.1% of control subjects as opposed to 33.9% of vulvar vestibulitis patients ( P =.0005). Similarly, after lipopolysaccharide stimulation, 70.2% of control subjects and only 48.4% of patients produced interferon-alpha ( P =.03). Among the positive samples, however, there were no differences in the interferon-alpha levels between patients and control subjects. In contrast, induction of interferon gamma in response to lipopolysaccharide was similar in control subjects (78.0%) and vulvar vestibulitis patients (82.1%). Women who have a deficiency in interferon-alpha production did not have an increased prevalence of human papillomavirus infection. There was no relation between interleukin-1 receptor antagonist genotype and interferon-alpha production. CONCLUSION: An inability to produce interferon-alpha may contribute to chronic vestibular inflammation in some women.