<i>Background:</i> Bacterial etiology of chronic rhinosinusitis (CRS) still remains controversial. Whereas <i>Staphylococcus aureus</i> enterotoxins have been detected in CRS, the impact of <i>Staphylococcus epidermidis</i>, a major commensal inhabitant of the nose, has not been studied. Among others, serine and cysteine proteases have been identified as factors of virulence in <i>S. epidermidis</i>. <i>Methods:</i><i>S. epidermidis</i> was examined in tissue biopsies of 30 CRS patients (16 with nasal polyposis) using standard procedures. Primary human nasal epithelial cells from inferior nasal turbinates (HNECs), from nasal polyps (NPECs) and A549 airway epithelial cells were stimulated with <i>S. epidermidis</i> supernatants DSM20044 or ATCC35984 and the IL-8 and GRO-α response was quanti- fied by ELISA. Protease-triggered chemokine responses and involvement of NF-ĸB were investigated by addition of protease or NF-ĸB inhibitors. Activation of NF-ĸB was demonstrated by quantitative DNA binding assay. <i>Results:</i><i>S. epidermidis</i> was the most frequently isolated bacteria in the majority of CRS patients. HNECs and NPECs revealed no different IL-6 and IL-8 synthesis following stimulation with DSM20044 or ATCC35984. Stimulation of HNECs and A549 cells with <i>S. epidermidis</i> supernatants resulted in increased IL-8 and GRO-α expression which could be suppressed by the serine protease inhibitor AEBSF and the NF-ĸB inhibitor BAY 11 but not by the cysteine protease inhibitor E64. Results obtained for A549 cells were similar to HNECs. <i>Conclusion:</i><i>S. epidermidis</i> was present in the majority of CRS specimens. Proinflammatory impact of <i>S. epidermidis </i>supernatants on nasal epithelial cells was demonstrated by serine protease-triggered and NF-ĸB-dependent chemokine responses.