BACKGROUND: The latex-fruit syndrome is a well-defined disorder whose genetic background has not been elucidated. OBJECTIVE: To study the genetic basis of the latex-fruit syndrome. METHODS: In a case-control study, we have investigated a carefully selected group of patients allergic to latex, searching for association between latex-fruit allergy and HLA class I and II genes, HLA-DR functional groups, and markers IL4-R1 and FcepsilonRI-betaca . RESULTS: Seventy-eight patients allergic to latex without spina bifida, 33% of them also allergic to fruits, were included in our protocol. Skin prick test results with both a commercial latex extract and purified hevein were significantly greater in patients allergic to latex and fruit than in patients allergic to latex and not fruit. A cutoff point of >7 mm for commercial latex skin prick test diagnosed latex-fruit allergy with a sensitivity of 66.7% (95% CI, 41.0-86.6) and a specificity of 83.3% (95% CI, 68.6-93.0) in our series of patients. No significant differences were found regarding HLA class I, IL4-R1 , or FcepsilonRI-betaca allele distributions. However, comparison of HLA class II allelic frequencies between patients allergic to latex and fruit and patients allergic to latex and not fruit showed significant associations of latex-fruit allergy with DQB1 *0201 (corrected P value, .001; odds ratio, 7.3; 95% CI, 2.6-20.0), as well as with HLA-DR functional group E (corrected P value, .028; odds ratio, 16.0; 95% CI, 1.9-134.1). When comparing allelic distribution among different subgroups of patients allergic to latex, additional significant associations of latex-fruit allergy with DRB1 *0301 and *0901, and of latex and not fruit allergy with DQB1 *0202, DRB1 *0701 and *1101, were demonstrated. CONCLUSIONS: Latex-fruit allergy is associated with HLA-DQB1 *0201, DRB1 *0301, and *0901, as well as with HLA-DR functional group E, whereas latex-not-fruit allergy is associated with DQB1 *0202, and with both DRB1 *0701 and *1101 alleles.