Fifteen healthy volunteers were inoculated enterally with trophozoites of two distinct human isolates of Giardia lamblia, GS/M and Isr. Each of two groups of five volunteers were inoculated with 50,000 (GS/M or Isr) trophozoites. All of the volunteers inoculated with GS/M and none of the volunteers inoculated with Isr became infected. Three of five volunteers infected with GS/M became ill, including two who had diarrhea and typical symptoms of giardiasis. In the second study, three patients who were previously infected with GS/M and treated were rechallenged 12 weeks after the first inoculation, together with five new control volunteers. All of the latter group became infected, and two developed loose stools; two rechallenged volunteers became reinfected but were asymptomatic, and a third was retrospectively found to be infected at the time of challenge. Serum IgM, IgG, and IgA antibody responses to Giardia and intestinal fluid IgA antibody responses to Giardia occurred in 100%, 70%, 60%, and 50%, respectively, of infected volunteers. These studies fulfill Koch's postulates and demonstrate strain variation in the pathogenicity of Giardia infections in humans.