Variations in antigen processing can influence class II-restricted T cell responses. We now report a highly significant difference (p < 0.001) between the ability of antigen-presenting cells from three HLA-DR4:Dw14.2 (Arg71) and six DR4:Dw4.2 (Lys71) individals to present recombinant or native acetylcholine receptor antigens to a myasthenia gravis T cell clone. The difference was greatest with longer antigens, and not seen with short synthetic peptides, suggesting that it may result from a difference in antigen processing between the two alleles. The results were not related to the presence of myasthenia gravis or of steroid therapy. They could, however, be of relevance in rheumatoid arthritis where particularly severe disease associates with Dw4.2/Dw14.2 heterozygosity.