The emergence of methicillin-resistant Staphylococcus aureus (MRSA) infections has created a need for additional antimicrobial options. Patients at the Minneapolis Veterans Affairs Medical Center, Minneapolis, MN, who received alternative (nonvancomycin, nonlinezolid) therapy for MRSA infections from January 2004 to December 2005 were identified retrospectively, with sulfamethoxazole/trimethoprim, clindamycin, tetracyclines, and fluoroquinolones assessed as alternative agents. Medical records were reviewed to determine therapeutic outcome and drug tolerance. During 2004 to 2005, 87 subjects received alternative therapy for MRSA infections. Infections included skin/musculoskeletal (n=74 [85%]) and urinary tract infections (n=13 [15%]). Thirty-five (40%) subjects received vancomycin initially, and then an alternative agent, whereas 52 (60%) received only alternative therapy. Treatment succeeded clinically in 77 (89%; 95% confidence interval, 78-96%) subjects. Adverse events were uncommon (6 subjects) and minor, necessitating a change of therapy in only 4 subjects. Alternative agents can be used successfully to treat non-life-threatening MRSA infections in appropriate patients. Randomized comparative trials are needed.