The red blood cell distribution width (RDW) is a routinely measured and automatically reported blood parameter, which reflects the degree of anisocytosis. Recently, the baseline RDW was found to have clinical significance for assessing clinical outcome and severity of various pathological conditions including cardiovascular diseases, sepsis, cancers, leukemia, renal dysfunction and respiratory diseases. A myriad of factors, most of which ill-defined, have an impact on the red cell population dynamics (i.e., production, maturation and turnover). A delay in the red blood cell clearance in pathological conditions represents one of the leading determinants of increased anisocytosis. Further study of RDW may reveal new insight into inflammation mechanisms. In this review, we specifically discuss the current literature about the association of RDW in various disease conditions involving the gastrointestinal and hepatobiliary systems. We also present some of the related measurements for their value in predicting clinical outcomes in such conditions. According to our data, RDW was found to be a valuable prognostic index in gastrointestinal disorders along with additional inflammatory biomarkers (i.e., C reactive protein, erythrocyte sedimentation rate, and platelet count) and current disease severity indices used in clinical practice.