Purpose: We previously identified BUN as the most accurate routine laboratory test for prediction of mortality in acute pancreatitis (AP) in a large multi-center retrospective cohort study. The purpose of this study was to: 1) confirm accuracy of BUN during first 24 hours for prediction of mortality in a rigorously defined prospective AP cohort and; 2) identify factors associated with increased BUN. Methods: Prospective cohort study of consecutive AP patients treated in a tertiary care hospital from June 2005-May 2007. AP was defined as 2 or more of the following: characteristic abdominal pain, amylase/lipase elevation >3 times upper limit normal and/or confirmatory imaging findings. Routine laboratory tests were monitored throughout hospitalization. Accuracy of BUN for prediction of in-hospital mortality was evaluated using logistic regression including admission BUN and change in BUN at 24 hours as discreet variables. Logistic regression was also used to determine the extent to which hydration (cc/kg first 24 hours), renal insufficiency (serum creatinine) or systemic inflammation (SIRS) contributed to increases in BUN. Results: We enrolled a total of 397 AP cases during the study period. Among these, 17% were hospital transfers. There were 15 (3.7%) deaths. A logistic regression model incorporating admission BUN and change in BUN at 24 hours produced an AUC of 0.91 for mortality. Both admission BUN and change in BUN were independent predictors of mortality (p<0.0001) after adjusting for age, gender, Charlson comorbidity score and hospital transfer status. Reduced fluid resuscitation (p=0.03), worsened renal insufficiency (p<0.0001) and SIRS (p=0.03) were independently associated with rise in BUN. Conclusion: We have prospectively confirmed the accuracy of early rise in BUN for prediction of mortality in AP. Rise in BUN is multi-factorial, reflecting intravascular volume depletion, renal insufficiency and systemic inflammation.