Pancreatic calcifications are virtually pathognomonic of chronic pancreatitis and develop in up to 90% of patients with alcoholic chronic pancreatitis in series with long-term results. We investigated the natural course of pancreatic calcification in a prospective longitudinal study over the past 23 yr. All patients were studied at regular intervals with particular regard to etiology, clinical findings, surgery, pancreatic function, and pancreatic calcification visible by x-ray (e.g., film series in three projections centered on the pancreas). We evaluated the findings of 107 patients with x-ray documentation of pancreatic calcification in at least three film series over a period of 4 yr or longer. Eighty-four patients had alcoholic chronic pancreatitis (group A) and 23 patients had nonalcoholic chronic pancreatitis (group B). Four hundred seventy-two film series of group A and one hundred forty-two film series of group B were reviewed independently by two expert teams. Both series were graded according to a score system in terms of intensity and distribution of pancreatic calcification (correlation of grading r = 0.91). The duration of calcification averaged 10 yr in group A and 12.6 yr in group B. Similar dynamic changes of pancreatic calcification were noted in groups A and B. Chronologically, three phases of evolution could be distinguished. After an initial increase (phase 1), greater than 50% of cases reached a plateau of stationary calcification (phase 2). Approximately one-third of cases showed a marked decrease of calcification in late phases of chronic pancreatitis (phase 3). Dissolution of pancreatic stones was related primarily to duration of chronic pancreatitis (duration of calcification and marked pancreatic dysfunction), and occurred frequently (but not exclusively) in patients after ductal drainage procedures. These results indicate that spontaneous dissolution of pancreatic stones is a rather common biologic phenomenon. The factors responsible for dissolution of stones remain to be elucidated.