Giardia lamblia is the most prevalent human intestinal protozoan worldwide, but only a minority of infections result in diarrhea. We tested here whether the 2 major G. lamblia genotypes, assemblages A and B, differ in their propensity to cause disease. To determine whether an association exists between infection with assemblage A or B and diarrhea, 2534 Bangladeshi patients were enrolled in a case-control study. A total of 322 Giardia infections were identified and assayed for genotype by real-time polymerase chain reaction. Higher odds ratios for diarrhea were observed for assemblage A and A2 infections, whereas higher parasite DNA loads and a higher overall prevalence were observed for assemblage B infections. Our findings indicate that genotypic differences in virulence and fecundity may help to explain why not every Giardia infection results in disease, but they need to be confirmed in other urban populations of the developing world.