At the University of Illinois Hospital, antibiotic susceptibility testing was retrospectively performed on 254 stored clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates cultured from 1985 through 1990 to characterize resistance to ciprofloxacin and other antibiotics. In case-control analyses, inpatients with and without ciprofloxacin-resistant strains were compared. Ciprofloxacin-resistance increased from 7% before 1988 to 83% in 1990. A sudden increase in resistance to trimethoprim-sulfamethoxazole also occurred in 1988, and by 1990, 65% of strains were resistant to both antibiotics. In 95 patients with recent MRSA isolation (70 acquired nosocomially, 25 acquired in the community), ciprofloxacin resistance was more common in the nosocomial group (80% v 60%, P < 0.05). In that group, no host or in-hospital factors were associated with ciprofloxacin resistance. Among community cases, a greater proportion with ciprofloxacin-resistant MRSA had diabetes mellitus (60% v 0%, P = 0. 002). Thus, with use, ciprofloxacin resistance emerged rapidly in MRSA and developed particularly among strains resistant to trimethoprim-sulfamethoxazole. Combined resistance to these antibiotics, uncommon in previous reports, severely limits oral therapy as an option for MRSA carriage or infection.