Chronic airway infections determine the outcome in cystic fibrosis (CF). We wanted to compare the quantitative composition of the upper and lower airway microbiome in mild and severe CF.Whole genome shotgun sequencing was performed on total DNA isolated from nasal lavage, oropharyngeal swab and induced sputum collected from exocrine pancreatic sufficient and exocrine pancreatic insufficient CF children and adults. Metagenomics identified CF disease-associated microbial communities in upper and lower airways, but a normal flora in the oral cavity. CF virome and mycobiome were dominated by phages, Candida and Aspergillus species, respectively. Staphylococcus epidermidis was the most prominent bacterium in the upper airways. Staphylococcus aureus and Pseudomonas aeruginosa were more abundant in lower than in upper airways. Four distinct groups prevailed by either S. aureus, P. aeruginosa, Haemophilus influenzae or anaerobes, could be discerned in the CF sputum of all age groups. Within the Veillonella, Prevotella, Rothia and Streptococcus genera the individual species were not equivalent in their impact on CF airway microbiome and disease. Prevotella melaninogenica was recovered more often and at higher abundance from CF patients with mild disease. The quantitative composition of the CF upper and lower airways microbiome differs by pancreatic status and disease severity.