Chronic rhinosinusitis (CRS) is a disease highly associated with abnormal regulation of T and B cells. The underlying pathophysiology of inflammatory pathways has critical implications for the diagnosis and management of CRS. Soluble CD40-ligand (sCD40L) is a cleaved form of CD40L present in plasma which functions the same way as CD40L, which has been observed as an inflammatory biomarker in many diseases. CD40L-positive cells control B-cell maturation, proliferation, apoptosis, and antibody production by binding to its receptor CD40 on B-cells. And our results show for the first time that patients with CRS have lower serum sCD40L levels compared to healthy subjects and that decreased sCD40L levels in patients correlate with increased CD40L-positive cell counts in the sinonasal mucosa. In addition, eosinophilic chronic rhinosinusitis (eCRS) patients tend to exhibit more CD40L-positive cells in the sinonasal mucosa compared to non-eCRS patients. This supports the notion that local blockade of CD40/CD40L may suppress pathogenic T/B cell responses and reduce tissue inflammation. Significantly, sCD40L and CD40L may be involved in the development and progression of CRS by impairing peripheral blood B-cell function and enhancing the local inflammatory response in the sinonasal mucosa.