Rationale: The randomized clinical trial has been an important tool for expanding our knowledge of disease. This study is the first to compare trial participants to the entire eligible population. Methods: We performed a cohort analysis using data from the Cystic Fibrosis Foundation Registry database from 1992 to 1998. Measurements and Main Results: There were 8,735 patients over six years of age followed for the entire period. Of the patients, 2,635 patients (30.2%) were enrolled in at least one of 32 IRB approved clinical trials with an average annual participation rate of 7%. Patients enrolled in clinical trials had more advanced disease as judged by FEV₁% predicted (68% vs 77%, p<0.001), higher rates of Pseudomonas aeruginosa infection (71% vs 65%, p<0.01), and were more likely to have private insurance (OR=1.25, 95% CI 1.14-1.37) and be Caucasian (OR=1.98, 95% CI 1.44-2.70). No gender differences were noted. Despite the worse clinical status at baseline, clinical trial participants had a lower average annual rate of decline in lung function (1.33% per year, 95% CI 1.20, 1.46 compared to 1.52%, 95% CI 1.43). Conclusions: These results show that the overall participation rate is very high. Despite more advanced disease at baseline, lung function decline was lower in trial participants; the cause of this difference is unclear. The differences seen in insurance status are concerning. Efforts should be made to ensure adequate representation from different social demographic groups.