OBJECTIVE To investigate the prevalence of HLA-D region antigens in patients with seronegative rheumatoid arthritis (RA). METHODS The distribution of HLA-D region antigens was studied in 33 patients with seronegative RA. All patients were followed for at least 3 years, during which tests for IgM rheumatoid factor were negative on at least 3 occasions. HLA-D region antigens were defined by serological and molecular techniques (oligonucleotide typing). RESULTS Our data demonstrate that DR4 was significantly (p < 0.021) increased in patients (45.5%) compared to normal controls (22.9%). Although the prevalence of DR1 was essentially the same in patients (15.2%) as in healthy controls (14.3%), the frequency of DR1 and/or DR4 was significantly (p < 0.018) increased in patients (60.6%) compared to healthy subjects (35.7%). The prevalence of remaining DR antigens and of DQ and DP specificities in patients with seronegative RA was not different from that in healthy controls. CONCLUSIONS Our results together with those published by other investigators suggest that both seropositive and seronegative RA are associated with DR4 and may therefore share the same immunogenetic bases.