Red cell distribution width (RDW) has been proposed as an early prognosis marker with increased mortality in variety of pathophysiological conditions. We hypothesized that elevated RDW could be used in judging the severity of acute pancreatitis (AP). We retrospectively and prospectively studied 545 and 72 AP patients, who were admitted to the Shanghai Tenth People's Hospital of Tongji University, respectively. Compared with mild acute pancreatitis, significantly higher RDW was observed in patients with moderately severe acute pancreatitis and sever acute pancreatitis (14.03 ± 1.74% vs. 13.23 ± 1.23%, P < 0.000). RDW values were also found positively correlated with the patient's blood urea nitrogen (r = 0.120, P = 0.026), creatinine (r = 0.182, P = 0.000), age (r = 0.099, P = 0.028), and bedside index of severity in acute pancreatitis scoring system (r = 0.147, P = 0.001), and were negatively correlated with the serum albumin (r = -0.244, P = 0.000). The area under the receiver-operating characteristics was as follows-RDW: 0.677 (95% confidence interval [CI], 0.619-0.735, P < 0.000); combination of RDW and albumin: 0.693 (95% CI, 0.625-0.761, P < 0.000); and the optimal cutoff value for RDW to predict whether patients with AP should be in intensive care unit (ICU) was 13.55 with a sensitivity of 54.5% and a specificity of 73.6%. In the validation study, AP with RDW ≥ 13.55% had significantly higher ICU admission ratio than those with RDW < 13.55% (44.4% vs. 9.8%, P < 0.000). In conclusion, RDW is positively associated with AP severity, and is likely a useful predictive parameter of AP severity.