Background: To compare vancomycin pharmacokinetic parameters in patients with and without neutropenia. Methods: Patients >= 18 years admitted on general wards were included. Routinely vancomycin trough and peak plasma concentrations were measured with a fluorescence polarization immunoassay. Pharmacokinetic parameters of individual patients were determined with maximum a posterior Bayesian estimation (MW Pharm 3.60). Neutropenia was defined as neutrophils <0.5X10(9) cells/L. Principal Findings: A total of 171 patients were included. Patients with neutropenia (n = 56) had higher clearance of vancomycin (CLva), 67 (+/- 26) mL/min, compared to patients without neutropenia (n = 115), CLva 50 (622) mL/min (p, 0.001). No significant difference was found in serum creatinine and vancomycin volume of distribution. Neutropenia was positively associated with CLva, independently of relevant co-variables (B: 12.122, 95% CI: 1.095 to 23.149, p = 0.031). On average patients with neutropenia needed 33% higher doses of vancomycin to attain adequate exposure, i.e. AUC(24)>= 400 mgxh/L. Furthermore, 15 initially neutropenic patients in our study group received vancomycin for a second administration period. Ten patients received the second administration period during another neutropenic period and 5 patients during a non-neutropenic phase. All 5 patients with vancomycin during both neutropenic and non-neutropenic phase had higher CLva (91 (+/- 26) mL/min) during the neutropenic period and lower CLva (45 (+/- 10) mL/min) during the non-neutropenic phase (p = 0.009). Conclusion: This study shows that most patients with neutropenia have augmented CLva. In a small group of patients that received vancomycin during two episodes, the augmented CLva seems to be reversible in the non-neutropenic period. Our data indicate that it is important to increase the daily dose with one third in patients with neutropenia (from 15 mg/kg twice daily to 13 mg/kg three times daily). Frequent performance of therapeutic drug monitoring in patients with neutropenia may prevent both therapy failure due to low AUCs and overcomes toxicity due to high vancomycin trough concentrations during recovery from neutropenia.