Introduction Biomarkers, which were introduced in the diagnosis and risk assessment of sepsis, could contribute toward predicting outcome in those patients affected by sepsis, severe sepsis, and septic shock who could benefit from a quick and appropriate therapy. Among different molecules that have been suggested as sepsis biomarkers in the last few years is red cell distribution width, which appears quite promising because of its reported correlation with the septic process. The aim of this study was to compare between red cell distribution width, C-reactive protein (CRP), and procalcitonin as diagnostic and prognostic markers in sepsis. Patients and methods This study was carried out on 45 adult patients of both sexes who had sepsis, severe sepsis, and septic shock; all of them received the same treatment as recommended by the surviving sepsis campaign; 17 of these patients have survived and the other 28 did not survive (group I). There were 45 healthy adult volunteers (group II). The patients in the study group were those who were admitted to the units of the Critical Care Medicine Department in Alexandria Main University Hospital and who fulfilled the diagnostic criteria for severe sepsis or septic shock on arrival to ICU according to the SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Venous blood samples were obtained from group I on admission, day 5, and day 10 to determine red blood cell distribution width (RDW), CRP, and procalcitonin levels on admission, day 5, and day 10; the Sequential Organ Failure Assessment (SOFA) score was also measured on days 1, 5, and 10. The APACHE II score was measured only on admission. Patients were managed according to the surviving sepsis campaign guidelines. Results On comparing the biomarkers studied in both groups, it was found that the values of RDW, CRP, and procalcitonin were significantly different between group I on admission and group II. CRP was less accurate than RDW and procalcitonin in assessing the severity of sepsis at admission. The best diagnostic cut-off for RDW on admission was 15.3%: at that level, sensitivity and specificity were 86.6 and 71.1%, respectively. The best diagnostic cut-off for CRP on admission was 39 mg/dl: at that level, sensitivity and specificity were 66.6 and 80%, respectively, and for procalcitonin, it was 1.4 ng/ml; at that level, sensitivity and specificity were 88.8 and 91.1%, respectively. Higher RDW values were found in patients with higher APACHE II and SOFA scores. RDW, the APACHE II score, and the SOFA score were significantly higher in nonsurvivors in comparison with survivors (P = 0.011, P Conclusion RDW is a new promising and readily available cheap biomarker that can aid the diagnosis of sepsis and also aid prediction of outcome comparable with more complex clinical scores (APACHE II and SOFA).