Background: Cancer in patients with cystic fibrosis (CF), the most common genetic disorder in Caucasians, has been a rare event. However, more patients now reach adulthood, and more patients undergo organ transplantation - factors associated with an increased cancer risk. Our aim was to assess the risk of cancer in nontransplanted and transplanted CF patients. Methods: We followed 28 858 patients whose data were reported to the Cystic Fibrosis Foundation patient registry from 1990 through 1999 and compared the number of cancers observed in transplanted and nontransplanted patients to the number expected from population-based cancer incidence data. All statistical tests were two-sided. Results: In 202 999 person-years of observation of nontransplanted CF patients, 75 cancers were observed, but 69.7 were expected (standardized incidence ratio [SIR] = 1.1, 95% confidence interval [CI] = 0.8 to 1.4). Twenty-three digestive tract tumors were observed, but 4.5 were expected (SIR = 5.1, 95% CI = 3.2 to 7.6). More cancers than expected were observed of the small bowel, colon, and biliary tract but not of the stomach or rectum. We found that the deficit of non-digestive tract tumors was not statistically significant (52 observed versus 65.2 expected; SIR = 0.80, 95% CI = 0.6 to 1.0; P = .055). In 2725 person-years of observation of 1063 transplanted patients, 13 cancers were observed, but 2.05 were expected (SIR = 6.3, 95% CI = 3.4 to 10.8), and more digestive tract tumors (four observed versus 0.19 expected; SIR = 21.2, 95% CI = 5.8 to 54.2) and lymphomas (seven observed versus 0.16 expected; SIR = 44.0, 95% CI = 17.7 to 90.7) were observed than expected. Conclusions: We observed an increased risk of digestive tract cancers among adult CF patients, particularly of the small bowel, colon, and biliary tract. This increased risk appeared to be more pronounced in patients who had had an organ transplantation.