The clinical course of patients with cystic fibrosis (CF) with functionally similar mutations in the CF transmembrane conductance regulator gene is variable and must therefore relate to secondary genetic and environmental factors. We examined the hypothesis that polymorphisms of certain inflammatory mediator and regulatory genes affect clinical outcome by influencing the degree of end-organ damage. By studying the possible association between clinical outcome and angiotensin I-converting enzyme (ACE) and cytokine genotypes by amplification refractory mutation system-polymerase chain reaction, using stored DNA from 261 white patients with CF, we found that ultrasound features of cirrhosis occurred more frequently in patients with the high-producer (DD) rather than the low-producer (II) ACE genotype (odds ratio [95% confidence interval], 3.7 [1.2 to 12]). Moreover, significant pulmonary dysfunction (age at which FEV1 < 50%) was associated with the high-producer ACE genotype (2.3 [1.2 to 4.5]) and transforming growth factor-beta1 genotype (2.6 [1.0 to 6.8]) as well as with age at first colonization with Pseudomonas aeruginosa (9.1 [1.1 to 72]). We conclude that the high-producer ACE genotype predicts patients with CF who have an increased chance of developing portal hypertension; and high-producer ACE and TGF-beta1 genotypes are secondary genetic factors contributing to pulmonary dysfunction in these patients.