Adaptation of bacterial pathogens to a permanently host-associated lifestyle by means of deletion or acquisition of genetic material is usually examined through comparison of present-day isolates to a distant theoretical ancestor. This limits the resolution of the adaptation process. We conducted a retrospective study of the dissemination of the P. aeruginosa DK2 clone type among patients suffering from cystic fibrosis, sequencing the genomes of 45 isolates collected from 16 individuals over 35 years. Analysis of the genomes provides a high-resolution examination of the dynamics and mechanisms of the change in genetic content during the early stage of host adaptation by this P. aeruginosa strain as it adapts to the cystic fibrosis (CF) lung of several patients. Considerable genome reduction is detected predominantly through the deletion of large genomic regions, and up to 8% of the genome is deleted in one isolate. Compared with in vitro estimates the resulting average deletion rates are 12- to 36-fold higher. Deletions occur through both illegitimate and homologous recombination, but they are not IS element mediated as previously reported for early stage host adaptation. Uptake of novel DNA sequences during infection is limited as only one prophage region was putatively inserted in one isolate, demonstrating that early host adaptation is characterized by the reduction of genomic repertoire rather than acquisition of novel functions. Finally, we also describe the complete genome of this highly adapted pathogenic strain of P. aeruginosa to strengthen the genetic basis, which serves to help our understanding of microbial evolution in a natural environment.