Vancomycin MIC creep has been reported by some institutions but not confirmed in large surveillance studies. We evaluated the possible occurrence of MIC creep when testing vancomycin and daptomycin against methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) by using precise incremental reference MIC methods. Nine hospitals (one in each U.S. census region) randomly selected bloodstream MRSA strains (target, 40/year) from 2002 to 2006. MICs were determined by the reference broth microdilution method using incremental dilutions (eight for each log(2) dilution step). Isolates for which vancomycin MICs were >1 microg/ml were typed by pulsed-field gel electrophoresis (PFGE). The vancomycin MIC mode was either 0.625 microg/ml (for eight hospitals) or 0.813 microg/ml (for one hospital), and vancomycin MIC results for 72.9% of strains were between 0.563 and 0.688 microg/ml. No yearly variation in the central tendency of vancomycin MICs for the wild-type population in any medical center was observed; however, when data were analyzed by the geometric mean statistic, vancomycin MIC increases (at three sites) and declines (at three sites) were observed. The daptomycin MIC mode varied from 0.156 microg/ml (2003 to 2005) to 0.219 microg/ml (2002 and 2006), and MIC results for 83.5% (80.3 to 89.2% in each of the centers) of isolates fell between these values. Among PFGE-typed strains, 43 of 55 (78%; from seven hospitals) showed a pattern consistent with that of the USA100 clone, which was represented by all strains from two hospitals and 64 to 88% of strains from five other medical centers; only one strain (2%) was USA300. In conclusion, the perception of MIC creep may vary according to the methods used to analyze the data. Geometric mean MIC data revealed a possible, very-low-level MIC creep at three of nine sites over the 5-year period, which was not evident using modal MICs or the data from all nine hospitals (+0.02 mug/ml). The occurrence of isolates for which the vancomycin MIC was >1 microg/ml was very unusual, with no increased trend, but these organisms were usually clonal (USA100).