Antibodies to denatured type II collagen were detected in the sera of a group of patients with rheumatoid arthritis by ELISA and by immunoblotting. The antibodies were further examined by immunoblotting against cyanogen-bromide derived peptides of type II collagen. The majority of sera reacted against only one or two peptides and antibodies to the CB-10 and CB-11 peptides were those most commonly found. However, some sera reacted with up to eight peptides, indicating that patients had antibodies to differing combinations of epitopes on type II collagen. Examination of sequential serum samples from an individual patient showed that there were changes in the class of antibody produced to type II collagen and that antibodies to different peptides were preferentially produced at different times in the course of the disease. Thus there was a selective response to different peptides of type II collagen not only between patients but also at different times in the course of disease in the same patient.