To date Paneth cells have not previously been reported to kill Giardia trophozoites and other protozoa in vivo. Here we report the first evidence for in vivo killing of Giardia trophozoites by intestinal Paneth cells. Transmission electron microscopic (TEM) examination of duodenal specimens taken from naturally infected mice revealed that only Giardia trophozoites harbouring peripheral bacterial endosymbionts were destroyed and lysed in the vicinity of the activated Paneth cells. Additionally, intestinal epithelium was more affected by Giardia harbouring bacterial endosymbionts than Giardia with no endosymbionts. Our findings imply that the bacterial endosymbionts within Giardia trophozoites have a role in both host protective and pathological mechanisms, probably through altering the trophozoite antigencity. These observations might shed light on the diversity in infectivity and host specificity of Giardia species.