Background: Chronic pancreatitis (CP) is a syndrome characterized by structural changes in the pancreas that lead to chronic abdominal pain and varying degree of pancreatic functional failure. It has difficult to assess the severity and progression of CP based upon pancreatic duct (PD) changes alone. The aims of this study were: (1) to develop a 'CP severity index' to assess the severity of CP; and (2) correlate the 'CP severity index' with different clinical outcomes in the natural history of CP. Patients and Methods: A prospective study of subjects with established CP was performed at the Pancreatitis Center of the VCU Medical Center, Richmond, VA. Baseline clinical, laboratory and radiologic findings were recorded. Patients were followed in the pancreatitis clinic at 6-month intervals or as the clinical situation warranted. Desirability function methodology was used to develop the CP severity score which ranges between 0 (most severe) and 1 (not severe). Of the 14 recorded variables, on the a stepwise ordinal logistic regression analysis, 8 variables were selected based on a stepwise ordinal logistic regression and combined into a 'pancreatitis severity score' alcohol use, side branch size, side branch ectasia (SBE >3),main PD (MPD) irregularity, MPD stricture, MPD leak, MPD calculi, and contour abnormality of the bile duct. The key outcomes assessed included: exocrine failure, endocrine insufficiency (diabetes), presence or development of a pseudocyst and bile duct stricture. An ordinal 'response' score was created at baseline and at one-year followup, which counted the number of the above outcomes in each patient. Results: Eighty nine subjects with CP (mean age 48 yrs, 54% males) were evaluated, of whom 48 (54%) were African American and 41 (46%) were Caucasian. On independent ordinal regression analysis, only the side branch size correlated with the severity of CP (p= 0.03). The 'CP severity score' significantly correlated with the number of adverse outcomes in CP (p=0.038) and was negatively associated with the number of outcomes. The average CP severity score in subjects with none, one, two, three and four adverse outcomes was 0.74, 0.70, 0.63, 0.60 and 0.43, respectively. For each 0.1 unit increase in the CP severity score the odds of moving to more adverse outcomes decreased by 0.85 times. Conclusions: The 'CP severity score' significantly correlates with the severity of CP. The 'CP severity index' reliably predicts the progression of CP by taking into consideration both imaging changes as well as behavioral risk factors as ongoing alcohol use.