HLA class II polymorphism is variably associated with sensitization to specific allergens, but few convincing HLA associations with asthma or the general state of atopy have been demonstrated. In this study we investigated HLA class II genotype associations with asthma, atopy and specific IgE (sIgE) production to six allergen extracts and six purified major allergens (Der p 1, Der p 2, Fel d 1, Can f 1, Alt a 1 and Phl p 5) in 176 individuals from 20 asthmatic family pedigrees. In selected individuals, cell surface HLA-DR peripheral B-cell expression was correlated with HLA-DRB1 genotype and atopic status. Results showed that HLA-DRB1*08 was negatively associated with asthma (2% vs 17%; Pc = 0.02; OR = 0.08) and atopy (0% vs 16%; Pc = 0.04; OR = 0.1), while DRB1*15 was positively associated with asthma (36% vs 13%; Pc = 0.02; OR = 3.6). Analysis of DRB1 sequences showed that only 29% of individuals with GAG TAC TCT ACG at codons 9-12 in one or both alleles were atopic, compared with 53% of individuals without this sequence (P = 0.002; OR = 0.36). DPA1*0201 was negatively associated with sIgE to both grass pollen mix and Phl p 5 (0% vs 23%; Pc = 0.02; OR = 0.14). A non-significant trend towards higher HLA-DR B-cell expression was seen in both non-atopic and DRB1*08 individuals. In conclusion, this single centre study has demonstrated a number of HLA class II genotype associations with asthma, atopy and sIgE to grass pollen mix and Phl p 5, including hitherto unreported DRB1*08, DRB1 codon 9-12 and DPA1*0201 associations. No significant associations between HLA-DR expression and DRB1 genotype or atopy were demonstrated, although a trend towards higher expression was seen in non-atopic individuals and individuals of DRB1*08 genotype.