Background: Asthma is a heterogeneous airway disease resulting from an interaction between multiple factors. Interferon-beta (INF-β) induces robust antiviral and immunomodulatory response to interfere with viral replication. The implication of nucleotide-binding oligomerization domain 2 (NOD2) was highlighted in many allergic diseases. Objective: The purpose of this study was to investigate the serum levels of INF-β and NOD2 single nucleotide gene polymorphism (SNP) among Egyptian asthmatic children who presented with wheezy and cough phenotypes. Methods: A group of 131 Egyptian asthmatic children (67 wheezy phenotype and 64 cough phenotype) together with 39 controls were enrolled and analyzed for the genotypes of NOD2 (rs2066845) polymorphisms using real time PCR via TaqMan assays. Serum INF-β levels were determined by ELISA technique. Results: Serum INF-β levels were significantly lower in both wheezy and cough phenotypes compared to control group (Z=1.19, p=0.233). Concerning the studied NOD2 SNP (rs2066845), both GG and GC genotypes showed significantly higher frequencies among asthmatic cases compared to healthy controls (p= 0.002, 0.021, respectively). Also, serum INF-β levels were significantly lower in both wheezy and cough asthma phenotypes with GG genotype compared to controls (p= 0.012, 0.015, respectively) of the same genotype. No significant differences were observed between the two studied asthma phenotypes regarding serum levels of INF-β, genotypes or allele frequency of NOD2 gene. Conclusion: Asthmatic children have lower levels of INF-β compared to controls, which might indicate a potential role of IFNs-based therapies for asthma. The study also provided possible evidence of the impact of rs2066845 G allele on asthma development.