Background:Giardia lamblia is a global enteric protozoan causing giardiasis, a disease characterized by different clinical presentations ranging from loss of appetite, abdominal pain, steatorrhea, nausea, vomiting to severe malabsorption syndrome, but the majority of infected children are asymptomatic, especially in developing countries. The clinical outcome may be associated with fecal calprotectin released in the bowel in case of inflammation and human leukocyte antigen (HLA) class-II DRB1 alleles that play a crucial role in the immune system. Objectives: To reveal any association between fecal calprotectin and the development of symptomatic or asymptomatic giardiasis. Also, to highlight the influence of HLA class-II DRB1 alleles on clinical manifestations of G. lamblia-infected children. Subjects and Methods: The study included 160 children: 80 healthy children (control), 40 Giardia-positive children with gastrointestinal symptoms (symptomatic group), and 40 Giardia-positive children without gastrointestinal manifestations (asymptomatic group). Fecal calprotectin was measured using ELISA, and HLA class-II was typed by PCR. Results: The commonest presentation of giardiasis was abdominal pain. Fecal calprotectin level was elevated (141.40±67.7-183±48.21 µg/gm) in children with giardiasis, mainly among asymptomatic group. HLA class-II DRB1*03:01 and *13:01 alleles were significantly associated with incidence of giardiasis (P<0.0005). A significant association of the heterozygous allotype HLA-DRB1*03:01/03:02 was recorded with giardiasis manifestations, mainly abdominal pain (P=0.026). Conclusion: Fecal calprotectin can be used as a marker of G. lamblia-induced intestinal inflammation. HLA class-II DRB1*03 and DRB1*13 alleles likely underlie clinical variability of giardiasis. This association may clarify why giardiasis does not occur in significant number of children exposed to the parasite.