Background: Over the past decade, an increasing trend in vancomycin minimum inhibitory concentration (MIC) levels for methicillin resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus has been reported. The phenomenon has been a topic of great interest in light of limited new and novel antimicrobial therapy in recent years. The goals of this study were to examine the relationship between high vs. low vancomycin MIC and patient outcomes, to assess the usage of vancomycin over time, and to determine whether an increase in vancomycin MIC had occurred among MRSA clinical isolates over time.Methods and Findings: A retrospective study was conducted from January 1, 1998 through December 31, 2008. Using the electronic medical record database, patients with blood, wound, or intravenous catheter tip cultures positive for MRSA during the study period were identified and reviewed. Variables abstracted from the electronic medical record for these patients included age, sex, site of culture, vancomycin MIC value, duration of vancomycin therapy, additional antibiotics prescribed,and co-morbidities including diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), malignancy, and liver disease. The DDD/100 days was calculated for the years 2002 through 2009. Two hundred andforty one (n=241) MRSA cultures were identified and used in the study. We identified a statistically significant upward trend in high vs. low vancomycin MICs from 1998 to 2008 (p<0.001). Past medical history of diabetes (RR=0.77, 95% CI, 0.57 to 1.02) was associated with Low vancomycin MIC compared to a high MIC, but did not reach statistical significance (p=0.07). History of liver disease (RR=0.40; 95% CI, 0.17 to 0.96)was associated with low MIC compared to a high MIC but did not reach statistical significance (P= 0.083). There was no statistically significant association between high and low MIC and 30 day mortality (p=0.21). There was a significant difference in mean vancomycin duration between those who died and those who survived (P= 0.0001), 8 vs. 18 days respectively. There was no statistically significant association between length of stay and high and low MIC (p=0.5). There was an increasing trend in vancomycin DDD/100 days from 2002 through 2009. Limitations of this study include the retrospective design and the almost exclusive male population (97%, 233/241).Conclusions: A significant upward trend in vancomycin MIC values over an 11-year period was identified at our institution. This trend was not associated with increased 30-day mortality or increased length of stay. An overall increase in the use of vancomycin (DDD/100 days) over the last eight years of the study period was also noted (range 2.4 to 4.3), suggesting a possible driving force for the increase in MIC. Larger,prospective, randomized studies would be helpful in substantiating these findings.