DNA and sera from 130 cases of gastric cancer and 263 population-based controls were analyzed to study the association of HLA class II DR-DQ alleles with Helicobacter pylori (Hp) infection and the risk for gastric cancer. Presence of the DQA1*0102 allele was inversely and significantly associated with Hp seropositivity (P = 2 x 10(-5)), which is an independent replication of previous findings. However, this inverse relationship with Hp did not correspond with a reduced risk of gastric cancer. At the DRB1 locus, the *1601 allele was significantly associated with an increased gastric cancer risk with an odds ratio (95% confidence interval) of 8.7 (range, 2.7-28.0). The effect of *1601 was more pronounced among Hp-negative subjects, and the association was stronger with the diffuse, rather than with the intestinal, histological type of gastric cancer. Because none of the HLA alleles were associated with both Hp infection and gastric cancer, the HLA DR-DQ alleles are linked with gastric cancer risk through other mechanisms than an increased susceptibility to Hp infection.