Background Peanut is one of the most common foods provoking allergic reactions and is the most frequent cause of fatal and near-fatal food-induced anaphylaxis. However, as yet, little is known of the genetic and immunological mechanisms which underly peanut allergy. Objective Based on findings in other allergic diseases, we have investigated whether particular human leucocyte antigen (HLA) class II genetic polymorphisms contribute to the development of peanut allergy. Methods All individuals from 37 families each containing one or more peanut allergic individuals, plus nine unrelated patients (161 individuals in total, defined as the study group) were typed for the HLA class II DRB1, DQB1 and DPB1 loci, by PCR-based techniques. Genotype frequencies were compared with those found in 293 unrelated controls. Results Four class II genotypes (DRB1*08 (13.7% vs 4.8%; Pc = 0.026), DRB1*08/12 tyr 16 (22.4% vs 8.2%; Pc = 0.021), DQB1*04 (12.2% vs 2.7%; Pc = 0.0026) and DPB1*0301 (49.1 vs 22.5%; Pc = 0.00062)) were present at a significantly higher frequency in the study group compared with controls. Three of these genotypes (DRB1*08 (18.0%; Pc = 0.027), DRB1*08/12 tyr16 (24.0%; Pc = 0.029) and DQB1*04 (16.7%; Pc = 0.0029)) were also significantly increased in peanut allergic individuals compared with controls. In addition, two genotypes (DPB1*0101 and 0201) were significantly decreased in frequency in the overall study group, but not specifically in peanut allergic individuals. Conclusion While other genetic factors may be important, results from this study indicate that HLA class II genetic polymorphism may play a role in determining susceptibility to peanut allergy.