OBJECTIVE To determine HLA-DQalpha and -DQbeta1 allele associations in juvenile-onset recurrent respiratory papillomatosis (RRP) for risk, disease course, and human papillomavirus type. METHODS A nonrandomized controlled study was performed on DNA extracted from papilloma specimens of children with a history of RRP, and from peripheral blood of African American and white children without RRP. The frequencies of DQalpha and DQbeta1 alleles were compared between patients and ethnically matched controls. METHODS Records of 48 children treated for RRP at Children's Hospital of Michigan in Detroit (26 African American and 22 white) were reviewed. Control subjects consisted of 80 African American and 80 white children seen at the hospital for conditions other than RRP. RESULTS African American and white patients with DQbeta1*050X (not *0501, *0502, *0503, *0504, or *0505) were at higher risk to develop RRP than controls (P =.01 and.03, respectively). DQbeta1*0402 was protective for African Americans (P =.01). Whites with DQalpha*0102 were at risk for RRP (P =.03). This allele was associated with disease remission in African Americans (P =.03). DQalpha*0101/0104 conferred protection in whites (P =.047). No association was seen for allele frequency and human papillomavirus type. Whites with haplotype DQalpha*0501/DQbeta1*0201 were at high risk for RRP (P =.002). No relationships were seen for African Americans or whites between haplotype frequencies and disease course or human papillomavirus type. CONCLUSIONS HLA-DQalpha and -DQbeta1 alleles occur at different frequencies in African American and white children with RRP than controls. Specific alleles influence risk for RRP. Allele and haplotype frequencies have some influence on disease course, but were independent of human papillomavirus type.