HLA-DR4 gene was studied by polymerase chain reaction method in 95 patients with rheumatoid arthritis(RA) and 130 normal controls in a Shanghai population. The results showed that the DR4 was significantly associated with RA(RR = 3.1, chi 2 = 13.8, P < 0.005). The second exon of DR4 gene was also analysed by PCR-RFLP technique. There were at lest eight DR4 subtypes in this Chinese population. The DRB1 *0405 (Dw15) was the most common allele, accounting for 48% of DR4 positive normal individuals and also is a principal subtype associated with RA susceptibility (RR = 3.1, P < 0.005). Analysis of the third hyperpolymorphic region of DR4 positive samples showed that 92% of patients had a sequence encoding amino acids RRAA or KRAA compared with 56% of the DR4 positive controls (chi 2 = 10.29 P < 0.005). All subtypes that were positively associated with RA susceptibility had the RRAA (DRB1* 0404, 0405. 0408 and 0410) or KRAA (DRB1 * 0401) sequences, while the negatively associated ones (DRB1 0402, 0403 and 0406) had not. As a further evidence, it strongly supported the "shared epitope" hypothesis. The different DR4 subtype structures and frequencies may account for the different associations of DR4 with RA in various ethnic groups.