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Chronic airway infections with Pseudomonas aeruginosa determine morbidity in most individuals with cystic fibrosis (CF). P. aeruginosa may persist for decades in CF lungs, which provides a rare opportunity to study the long-term within-host evolution of a bacterial airway pathogen. In this work, we sought to resolve the genetic adaptation of P. aeruginosa in CF lungs from the onset of colonization until the patient's death or permanent replacement by another P. aeruginosa clone. We followed the microevolution of the first persisting P. aeruginosa clone by whole-genome sequencing of serial isolates from highly divergent clinical courses of airway infection, i.e., a fatal outcome because of respiratory insufficiency within less than 15 years, or a rather normal daily life 25-35 years after acquisition of P. aeruginosa. Nonneutral mutations predominantly emerged in P. aeruginosa genes relevant for protection against and communication with signals from the lung environment, i.e., antibiotic resistance, cell wall components, and two-component systems. Drastic and loss-of-function mutations preferentially happened during the severe courses of infection, and the bacterial lineages of the mild courses more proficiently incorporated extra metabolic genes into their accessory genome. P. aeruginosa followed different evolutionary paths depending on whether the bacterium had taken up residence in a patient with CF and normal or already compromised lung function.