We have undertaken a case referent study of the association between HLA allele frequency and specific IgE antibody to acid anhydride-human serum albumin (AA-HSA) conjugates among acid anhydride workers. Thirty cases with radio-allergosorbent test score versus AA-HSA conjugates > 2 were compared with 30 referents without specific IgE selected from the same factory sites as the cases and matched for age, sex, duration of exposure, atopic status, and smoking habit. We found a significant excess of HLA-DR3 in the cases with specific IgE to acid anhydrides when compared with the referents (50% versus 14%, Fisher's statistic = 8.4; odds ratio = 6, p = 0.05 corrected). The excess of HLA-DR3 was particularly associated with IgE versus trimellitic anhydride, with HLA-DR3 present in eight of 11 workers with and in two of 14 referents without IgE (Fisher's statistic = 8.5, odds ratio = 16, p = 0.004). The proportion of HLA-DR3 among the phthalic anhydride workers was not different in those with IgE (two of 12) from their referents (two of 14). These findings suggest MHC II proteins are an important determinant of the specificity of the IgE response to an inhaled hapten.