SummaryBackground Organic acid anhydrides are low molecular weight industrial chemicals, able to cause rhinoconjunctivitis and asthma associated with specific IgE against hapten–carrier protein conjugate. Only a proportion of exposed workers develop IgE‐associated allergy to acid anhydrides.Objective We determined whether genetic susceptibility, in particular, HLA Class II alleles may be a risk factor.Methods We undertook HLA typing in 52 cases who had confirmed specific IgE and in 73 referents matched on site, age and duration of acid anhydride exposure identified in cross‐sectional studies of workers exposed to hexahydrophthalic (HHPA), methylhexahydrophthalic (MHHPA) and methyltetrahydrophthalic (MTHPA) anhydrides.Results The linked alleles DQ5 (odds ratio [OR]=4.3; 95% confidence interval [95% CI]=1.7, 11) and DR1 (OR 3.0; 95% CI 1.2, 11) were more prevalent in cases than in referents. Within DQ5, DQB1*0501 was particularly frequent (OR 3.0; 95% CI 1.2, 7.4).Conclusion DQB1*05 gene confers susceptibility to develop specific IgE antibodies against HHPA, MHHPA and a non‐significant trend with MTHPA. DQB1*0501 is protective for other low molecular chemical sensitizers (isocyanates and plicatic acid) which may indicate varying affinities for the corresponding specific class II molecules.