Objectives: To evaluate interleukin-1 and TNF- α serum levels and their single nucleotide gene polymorphisms (SNPs) association in patients with chronic rhinosinusitis. Methods: A case-control study performed between June 2022 and March 2023 at Benha University Hospitals, Benha, Egypt.  50 patients with chronic rhinosinusitis (CRS) with nasal polyps (Group 1), 50 patients with CRS without nasal polyps (Group 2), and 50 healthy volunteers as the control group (Group 3). TNF-α and IL -1 serum levels were detected by enzyme-linked immunosorbent assay (ELISA). Gene polymorphisms of cytokines IL-1 and TNF-α were delineated through the application of Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) methodology. Results: Serum concentrations of TNF-α and IL-1 exhibited markedly elevated levels in both groups 1 and 2 when compared with the control group, as evidenced by a highly significant statistical difference [p<0.0001]. Significant genotype distribution of TNF-a 308G>A SNP among (group 1,2) and controls (P < 0.001). The frequency of the GA genotype was found to be more prevalent in group 1 at 48% and group 2 at 50%, compared to a notably lower prevalence of 6% observed in the control group (group 3). Allele-A was significantly higher in groups 1 and 2 than in group 3. No significant differences found between IL-1A (+4845G/T) genotype distributions in groups 1 and 2 compared to group 3 (p = 0.093). The IL-1B (−511C/T) polymorphism shows a notable correlation in both groups 1 and 2 when compared to the control group (p < 0.001). Conclusion: Significantly higher TNF- α and IL-1 serum levels and TNF-α and IL-1B (-511C/T) polymorphisms with CRS with or without nasal polyps. Both IL-1B and TNF-α may be involved in the regulation of CRS etiopathogenesis and could represent novel therapeutic targets for its management.