Ciprofloxacin is one of the few drugs still effective against Salmonella infections. Ciprofloxacin binds the A subunit of type II topoisomerase enzymes, primarily GyrA (DNA gyrase) in Gram-negative bacteria and ParC (topoisomerase IV) in Gram-positive bacteria. Interaction of ciprofloxacin with topoisomerases disrupts enzyme function resulting in double stranded breaks in the chromosome, relaxation of DNA supercoiling, and the cessation of DNA replication. We tested the growth of Salmonella enterica SL1344 and mutants, fis, crp and rpoS, in LB containing 0%, 0.5% and 1% NaCl and sublethal concentrations of the antibiotics novobiocin, nalidixic acid, and ciprofloxacin. We observed that a Salmonella enterica mutant lacking the cyclic AMP receptor protein (crp) gene was less susceptible to ciprofloxacin than wild type. We tested two hypotheses to explain this antibiotic resistance phenotype: I) a Δcrp mutant has reduced permeability to small molecule antibiotics, or II) a Δcrp mutant is pre-adapted to the ciprofloxacin challenge by virtue of having a decreased level of drug target. The first hypothesis was addressed by testing if the Δcrp mutant was also resistant to the ribosome-targeting antibiotics tetracycline and kanamycin. There was no difference in susceptibility between Δcrp and wild type to either drug. Quantitative PCR revealed that expression of the major porin, ompC, was unchanged in the Δcrp mutant, but ompA and ompF decreased. Expression of the drug efflux pump acrB was also found to increase in the mutant. Using twodimensional chloroquine gel analysis, we determined that DNA supercoiling was more relaxed in the Δcrp mutant than in wild type, supporting the second hypothesis. Although DNA gyrase (gyrA and gyrB) and topoisomerase I (topA) expression was similar in both the Δcrp mutant and wild type, the secondary topoisomerase genes, parC and parE, were more highly expressed in the Δcrp mutant. We also observed that wild-type cells treated with ciprofloxacin had a filamentous phenotype after 12 h, while cell division in Δcrp cells was unaffected. Filamentous growth is suggestive of the SOS response and has been observed in cells treated with ciprofloxacin. Therefore, we verified expression levels of two SOS response proteins, sulA and ftsA. Although we observed the filamentous phenotype in wild-type cells, sulA and ftsA expression did not conclusively indicate that the SOS response had been initiated in wild type. Together, these data support a model in which Δcrp mutants are resistant to the effects of ciprofloxacin due to DNA relaxation arising from increased expression of topoisomerase IV (parCE), reduced permeability (ompA and ompF) and increased efflux of ciprofloxacin (acrB).