We comparatively evaluate the effect of metronidazole (MTZ) and its five analogues on trophozoites of Giardia lamblia axenically growing. The compounds MTZ-Ms, MTZ-I, MTZ-Br, MTZ-N(3), and MTZ-NH(3)Cl were obtained by molecular modification of the side chain of MTZ. Four of them presented higher giardicidal activity when compared with MTZ. Among them, MTZ-Br and MTZ-I were the most active, without cytotoxic effects against mitogen-activated human peripheral blood mononuclear cells (PBMC). The alteration of MTZ side chain constitutes a fruitful field to develop new drugs for the treatment not only of giardiasis but also of other diseases and signalize that metronidazole analogues are promising candidates as giardicidal and should be further evaluated.