Extensive analysis of rhinovirus genome modification was performed in the case of one patient (F78) infected for more than two years with a HRV-A9 strain. Phylogenetic analysis of 11 complete genome sequences (including ultra-deep sequences performed at three different time points) revealed that the URT and LRT populations were phylogenetically indistinguishable for a prolonged period of time, either because of co-variation or, more likely, constant viral population mixing. Once potentially adapted to the host through the accumulation of non-synonymous changes mainly in the capsid gene VP1, the viral populations appeared to evolve more slowly. Finally, we observed signatures of putative adaptation to lower airway conditions after several months of infection. Indeed, the last two LRT populations studied presented specific changes in the 59UTR polypyrimidine tract and two non-synonymous changes, one in the VP2 immunogenic site 2 and the second in protein 2A. These changes were absent in the URT population and, upon their appearance, the two populations remained separated as confirmed by ultra-deep sequencing analysis. Although the direct impact of these changes on virus growth ability at lower airway conditions remains to be demonstrated experimentally, the very high viral load observed at this stage suggests that both populations were adapted to their sites.