Helicobacter pylori is now recognized as the primary etiological factor associated with gastritis, peptic ulcer disease and gastric cancers. Fluoroquinolones have been shown to be active against H. pylori. For develop new anti-H. pylori agents, we have investigated the SAR of a series of N-(phenethyl)piperazinyl quinolones for their antimicrobial activity against H. pylori. The anti-H. pylori activity of synthesized compounds along with commercially available anti-H. pylori agents such as metronidazole, and parent quinolones was evaluated by the disc diffusion bioassay. The results indicated that the potency and anti-H. pylori activity profile of the quinolones is highly dependent on the type of substituent at N-1 and the structure of phenethyl unit on piperazine ring. Most compounds containing a cyclopropyl at N-1 exhibited good activity against H. pylori strains. Among them, ciprofloxacin derivative 13 containing 2-methoxyimino-2-(2-chlorophenyl)ethyl moiety was the most active compound.