Objective: To compare the genotype frequencies of HLA class- II DRB1 alleles in Giardia (G.) lamblia-infected children. Methods: A total of 490 Egyptian children aged 2-16 years were subjected to microscopic stool examination to detect G. lamblia infection, and to exclude other intestinal pathogens. On the basis of their microscopic findings, a group of 80 children were chosen as giardiasis cases, another 80 children were confirmed as Giardia free control group by immunochromatographic test, and the remaining children were excluded. Both giardiasis and control groups were then subjected to blood examination to identify their genetic type of HLA-DRB1 alleles. Results: HLA class-II DRB1∗03:01 and DRB1∗13:01 alleles were significantly associated with G. lamblia infection (P<0.001 for each variable). On the other hand, HLA class-II DRB1∗04:02, DRB1∗10:01, DRB1∗14:01 and DRB1∗15:01 alleles were significantly demonstrated in Giardia free children. However, other HLA-DRB1 alleles did not show any significant association with giardiasis. Conclusions: HLA class-II DRB1∗03, DRB1∗13, DRB1∗04, DRB1∗10, DRB1∗14 and DRB1∗15 alleles may be involved in the establishment of host immune response to G. lamblia infection.