The fluoroquinolones, particularly ciprofloxacin, have been suggested to treat methicillin-resistant Staphylococcus aureus (MRSA) infections and colonization and methicillin-susceptible S. aureus (MSSA) infections. The development of ciprofloxacin resistance in MRSA and MSSA was prospectively evaluated. After 3 months of ciprofloxacin use, high-level resistance (MIC90, 64 micrograms/ml) developed in MRSA and increased at an alarming rate, from none to 79% over a 1-year period. High-level ciprofloxacin resistance also developed in MSSA, increasing to 13.6% over the same period. Antibiograms, phage typing, and plasmid profile analysis suggest that more than one clone of MRSA developed resistance and that ciprofloxacin resistance is not associated with the acquisition of a new plasmid. Most patients had nosocomial acquisition and about one-half had a history of previous ciprofloxacin use. Ciprofloxacin resistance can develop rapidly in S. aureus; thus, ciprofloxacin appears to have limited usefulness in treating staphylococcal infections and colonization, especially those due to MRSA.