Background: Cystic Fibrosis (CF) is a common genetic disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein. It is known that modifier genes and environmental factors play a key role in determining the severity of the disease. Methods: We analyzed Single Nucleotide Polymorphisms (SNPs) in three genes, namely TNFA, TGFB1 and ADRB2, as potential modifiers of CF lung phenotype: c.−851C>T, c.−308G>A, c.−238G>A and c.+691G ins/del SNPs in TNFA, p.Leu10Pro (c.869C>T) and p.Arg25Pro (c.915G>C) SNPs in TGFB1 and p.Arg16Gly (c.46G>A), p.Gln27Glu (c.79C>G) and p.Thr164Ile (c.491C>T) in ADRB2. Results: For the c.46G>A SNP of ADRB2 the A allele (Arg16), as well as the AA genotype, were significantly more frequent in CF patients than healthy controls. When stratifying CF patients according to FEV1 (Forced Expiratory Volume in 1 second) phenotype we observed a statistically significant difference (p=0.02) in the allelic and genotype frequencies. The A allele and A/A genotype were more frequent in mild CF patients when compared to severe CF subjects and thus probably associate with a protective effect toward the development of severe pulmonary manifestation in CF patients. Conclusions: Our results are indicative of the involvement of the ADRB2 gene as modifier gene in Cystic Fibrosis pulmonary phenotype.