Selection and regrowth of ciprofloxacin-resistant variants, which were present in low frequencies in the initial inoculum, were seen when large inocula of Pseudomonas aeruginosa were incubated with ciprofloxacin. These variants showed cross resistance to other quinolones. In 8 of 13 strains tested, ciprofloxacin selected imipenem-resistant variants in a similar way to imipenem. The opposite phenomenon of ciprofloxacin-imipenem cross resistance after exposure to imipenem was not detected. None of the ciprofloxacin-resistant variants showed cross resistance to aztreonam, piperacillin, or tobramycin. These findings indicate that widespread and uncritical use of ciprofloxacin gives a potential risk of development of resistance in P. aeruginosa not only to quinolones but also to another unrelated useful agent, imipenem. In vitro evaluation of this phenomenon in isolates from patients with P. aeruginosa infections may be justified, since strains differ in development of quinolone-imipenem cross resistance after ciprofloxacin exposure.