Five fluoroquinolones were tested against 300 staphylococci from a wide variety of US medical centers including 150 strains resistant to penicillinase-resistant penicillins (PRP-resistant). Ten ciprofloxacin-resistant strains of PRP-resistant Staphylococcus aureus were relatively resistant to the other fluoroquinolones, but the remaining 290 isolates were susceptible to all five drugs at established or anticipated breakpoint concentrations. The relative potency of the study drugs could be ranked as follows: CI-960 > PD 131628 > sparfloxacin > ciprofloxacin > ofloxacin. All five drugs were bactericidal against PRP-resistant and PRP-susceptible staphylococci.