The in-vitro activities of five investigational antibiotics, RP59500 (a semisynthetic injectable streptogramin), CL 329,998 and CL 331,002 (two new glycyclyclines), trovafloxacin (a naphthyridone), and clinafloxacin (a dihalogenated quinolone), were examined and compared with those of minocycline, teicoplanin and vancomycin against 190 clinical isolates of Grampositive cocci. The MICs for RP59500 against all isolates with the exception of Enterococcus faecalis were low. RP59500 was bactericidal against all except enterococcal isolates. CL 329,998 and CL 331,002 were significantly more active than minocycline against oxacillin-resistant Staphylococcus aureus (MIC90 0.25 versus 8 mg/L) and all enterococcal isolates (MIC90 0.125 versus 16 mg/L). Clinafloxacin was the most active agent against all staphylococcal isolates and was bactericidal. Trovafloxacin showed good activity against oxacillin-susceptible staphylococci and a-haemolytic streptococci (MIC90 ≤ 0.125 mg/L). This study demonstrates the potential of the five investigational antibiotics as therapeutic agents for infections caused by Gram-positive cocci.