We studied serial measurements of serum cationic trypsinogen in patients with cystic fibrosis to assess the predictability of changes in individuals and the value of longitudinal measurement in defining pancreatic status. Three hundred twenty-nine patients with cystic fibrosis, aged 3 days to 40 years, had serum levels of trypsinogen measured on 2 to 12 occasions for periods ranging from 1 week to 7 years. Patients were classified into three groups on the basis of 72-hour fecal fat studies performed at the time of diagnosis. Two hundred thirty-three patients had pancreatic insufficiency (PI), 78 had pancreatic sufficiency (PS), and 18 had PS at diagnosis but acquired PI during follow-up (PS-->PI). Infants with PI had greatly elevated serum trypsinogen levels that fell sharply in the first years of life, so that by age 7 years more than 95% had subnormal values; individual patient values followed a predictable course similar to previously reported cross-sectional age-related values. In patients with PS, serum trypsinogen levels generally remained within or above the normal range and, after age 10 years, were well above the upper limit for PI patients. Within-patient variance was significantly greater (p < 0.0001) in patients with PS than in those with PI who were older than 7 years of age. Changes in patients within PS-->PI generally followed the pattern seen in patients with PI, but values in older patients tended to be in the higher range. We concluded that serial measurement of serum trypsinogen is a valuable tool for monitoring the pancreatic status of patients with cystic fibrosis and PS.