A strong independent association has been recently observed between elevated red blood cell distribution width (RDW) and increased incidence of cardiovascular events. To assess whether RDW is associated with plasma markers of inflammation since the mechanism(s) underlying this association remain unknown. We retrospectively analyzed results of RDW, hemoglobin, mean corpuscular volume, ferritin, high-sensitivity C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) in a large cohort of unselected adult outpatients who were consecutively referred by general practitioners for routine medical check-up. Cumulative results of RDW and other factors were retrieved from the database of our laboratory information system for 3845 adult outpatients during a 3-year period. When participants were grouped according to RDW quartiles, there were strong, graded increases of ESR and hsCRP (P < .001), both parameters being up to 3-fold higher in the fourth versus the first quartile. Accordingly, the percentages of those with hsCRP greater than 3 mg/L (from 28% to 63%; P < .001) and ESR greater than 40 mm/h (from 8% to 40%; P < .001) increased steadily across RDW quartiles. In multivariable regression analysis, ESR and hsCRP predicted RDW independently of age, sex, mean corpuscular volume, hemoglobin, and ferritin. To our knowledge, our study demonstrates for the first time a strong, graded association of RDW with hsCRP and ESR independent of numerous confounding factors. If confirmed in future follow-up studies, this association might provide a rationale to introduce the easy, inexpensive RDW in algorithms for cardiovascular risk prediction.